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THE    BLOOD 


PRINTED    BY 

GREEN     AND     SON 

EDINBURGH 


Oduber  HU4 


THE    BLOOD 

A    GUIDE    TO    ITS    EXAMINATION    AND    TO 

THE    DIAGNOSIS    AND    TREATMENT 

OF    ITS    DISEASES 


BY 

G.  LOVELL   GULLAND,  M.A.,  B.Sa,  M.D.,  F.E.C.P.E. 

SENIOR   LECTURER   ON   CLINICAL   MEDICINE   IN  THE   UNIVERSITY  ;   PHYSICIAN  TO   THE   ROYAL   INFIRMARY 

AND   TO   THE   ROYAL   VICTORIA   HOSPITAL  FOR   CONSUMPTION  ;   HONORARY   PHYSICIAN  TO   CHALMERS' 

HOSPITAL;    LECTURER   ON  MEDICINE   AT   SURGEONS'   HALL,    EDINBURGH 

AND 

ALEXAKDEE   GOODALL,  M.D.,  F.E.C.P.E. 

ASSISTANT  PHYSICIAN  TO  THE  ROYAL  INFIRMARY  ;   LECTURER  ON  PHYSIOLOGY  AT  SURGEONS'  HALL, 

AND   ON  DISEASES   OF   THE   BLOOD   IN  THE   EDINBURGH   POST-GRADUATE   COURSES   IN   MEDICINE; 

EXAMINER   IN   PHYSIOLOGY   IN   THE   ROYAL   COLLEGE   OF   PHYSICIANS,    EDINBURGH 


WITH   TWENTY-EIGHT  TEXT  ILLUSTRATIONS  AND  SIXTEEN 
COLOURED  PLATES 


SECOND    EDITION 


E.    B.    TREAT    &   COMPANY 

MEDICAL   PUBLISHERS 

NEW    YOEK 

1915 


Digitized  by  the,  Wernat  Archive 

in  2010  witrrfundin§  from 

Open  Knowl^f^TCommons 


http://www.archive.org/details/bloodguidetoitseOOgull 


PREFACE   TO   THE   FIRST   EDITION 

Our  aim  in  writing  this  book  has  been  to  put  in  the  hands  of  the 
student  and  practitioner  a  volume  giving  a  concise  and  clear  account 
of  the  diseases  and  diseased  conditions  of  the  blood  and  blood-forming 
organs,  based  on  a  large  experience  of  them  in  clinical  work  and  in  the 
laboratory. 

We  have  for  many  years  conducted  post-graduate  courses  on  the 

subject,  and  have  learned  how  essential  to  a  proper  understanding  of  the 

blood  and  its  diseases  are  a  knowledge  of  pathology,  and  a  clear  idea  of 

the  relationship  of  the  different  elements  of  the  blood  to  one  another,  and 

of  their  genesis.    We  have  tried  to  keep  our  descriptions  of  these  matters 

as  simple  as  possible,  and  to  avoid  the  excesses  of  differentiation  and 

nomenclature  in  which  some  writers  have  indulged.     Our  explanations 

may  not  be  finally  correct,  but  we  have  at  least  found  them  serviceable 

to  ourselves  and  others  as  working  hypotheses,  and  our  aim  throughout 

has  been  rather  to  stimulate  interest  in  a  fascinating  branch  of  study 

than  to  make  a  final,  erudite,  and  conclusive  exposition  of  the  subject. 

For  this  reason  we  have,  in  the  section  on  methods,  described  fully 

those  which  we  have  found  essential  or  useful,  and  in  the  case  of  those 

which  we  have  felt  to  be  less  important  have  referred  readers  to  the 

original  sources  of  information.     In  the  same  way  we  have,  so  far  as  it 

is  possible  in  a  work  of  this  kind,  relied  in  our  descriptions  on  our  own 

clinical  and  pathological  experience  rather  than  on  a  collation  of  the 

views  of  others,  and  we  have  given  only  those  references  which  seemed 

to  us  essential.      It  would  indeed  be  impossible  to  give  a  full  list  of 

papers  on  such  subjects  as  pernicious  anasmia  or  the  leukaemias,  nor  is 

it  necessary  to  do  so,  as  since  1904  the  world's  hematological  literature 

has  been  collected  and  summarised  in  the  Folia  Hc&matologica. 

In  dealing  with  the  alterations  in  the  blood  in  general  diseases  as 
an  aid  to  diagnosis,  we  have  felt  justified  in  stating  our  conclusions 

<r 

\r 


vi  PEEFACE   TO   THE   FIEST  EDITION 

categorically,  as  we  have  for  many  years  neglected  no  opportunity  of 
testing  the  views  of  others  and  amplifying  our  own  knowledge. 

We  have  made  no  attempt  to  deal  with  serology,  as  that  subject 
passed  long  ago  out  of  the  hands  of  the  clinician,  and  is  only  now 
beginning  to  return  to  him  in  the  shape  of  reactions,  the  value  of 
which  is  in  many  cases  as  yet  unproved. 

We  trust  that  the  sections  on  treatment  will  be  found  useful ;  in 
them  also  we  have  relied  mainly  on  our  own  experience. 

G.  L.  G. 
A.  G. 
Edinburgh, 

May  1912. 


PREFACE   TO   THE   SECOND   EDITION 

In  preparing  this  edition  the  whole  book  has  been  revised  and  in  several 
parts  rewritten.  Additions  to  the  extent  of  about  fifty  pages  have  been 
made,  and  twelve  new  illustrations  have  been  introduced. 

Among  the  new  matter  will  be  found  an  account  of  new  counting 
apparatus,  dark-ground  illumination,  the  oxydase  reaction,  anaplasmata, 
and  v.  Schilling-Torgau's  views  on  erythrocyte  structure.  The  latter 
are  as  yet  unconfirmed,  but  they  seem  to  us  to  indicate  lines  of  research 
which  may  yield  results  of  practical  importance. 

In  view  of  the  attention  now  being  paid  to  the  primitive  forms  of 
white  cells  in  leukaemia,  we  have  augmented  the  description  of  these 
cells,  but  we  are  not  convinced  of  the  clinical  importance  of  many  of 
the  histological  refinements.  Our  views  on  this  subject  are  stated  on 
pp.  193  and  194. 

After  the  chapter  on  Pernicious  Ansemia  was  in  type  the  question 
of  splenectomy  in  that  disease  began  to  assume  some  importance.  It 
has  therefore  been  discussed  in  an  Appendix. 

G.  L.  G. 
A.  G. 
October  1914. 


CONTENTS 

PART   I 

Methods  of  Examining  the  Blood 

CHAPTER   I 

Examination  op  Fresh  Specimens  :    Enumeration  of  Red  Corpuscles 

Withdrawal  of  samples  of  blood,  1  ;  examination  of  fresh  blood,  rouleaux  forma- 
tion, shape  and  size  of  the  cells,  2  ;  proportions  of  the  different  corpuscles, 
fibrin  network,  enumeration  of  red  corpuscles,  diluting  fluids,  3  ;  hsemocyto- 
meters  of  Thoma,  Biirker,  Zappert,  Turk,  and  Gowers,  4  ;  pipettes  of  Durham, 
Hirschfeld,  and  Pappenheim,  Oliver's  tintometer,  11  ;  the  hematocrit,  the 
volume  index,  13. 

CHAPTER    II 

Enumeration  op  Leucocytes  and  Blood-Plates 

The  leucocytometer,  diluting  fluid,  14  ;  methods  of  Turton,  Biirker,  Strong  and 
Seligman,  16  ;  enumeration  of  blood-plates,  17  ;  diluting  fluids,   17. 

CHAPTER    III 

Estimation  op  Haemoglobin  :   The  Colour  Index  :    Care  op  Instruments 

Hcemoglobinometers  of  Gowers,  Haldane,  Sahli,  v.  Fleischl,  Fleischl-Miescher,  Oliver, 
Dare,  Tallqvist,  and  Hall,  18  ;  the  ferrometer,  24  ;  other  hsemoglobinometers, 
the  colour  index,  24  ;  the  care  of  instruments,  25. 

CHAPTER    IV 

Examination  op  Stained  Films — Procedure  at  the  Bedside 

Spreading  the  film,  27  ;  preparation  of  dry  films,  fixation,  29  ;  staining — eosine  and 
methylene  blue,  Romanowsky  effect,  Giemsa,  Ehrlich's  triple  stain,  heematein 
and  eosine,  iron  hematoxylin,  30  ;  combined  fixing  and  staining  methods— 
Jenner,  Leishman,  34  ;  panchromic  mixtures — Jenner-Gienisa,  Pappenheim  ; 
wet  methods,  35  ;  choice  of  staining  methods,  36  ;  procedure  at  the  bedside,  37. 


x  CONTENTS 

CHAPTER   V 

Special  Methods  of  Examination 

Viscosity  of  the  blood,  38;  estimation  of  coagulation  time — methods  of  Sabrazes 
and  M'Gowan,  Wright,  Buckmaster,  Addis,  Lee  and  White,  and  others,  39  ; 
alkalinity  of  the  blood — method  of  Rigler,  Drouin,  Dare,  Boycott  and  Chisolm, 
41  ;  specific  gravity  of  the  blood,  43  ;  cryoscopy,  44  ;  fragility  of  .the  red  cor- 
puscles, 46  ;  total  quantity  of  blood  in  the  body,  47  ;  bacteriological  examina- 
tion of  the  blood,  47  ;  dark-ground  illumination,  48  ;  glycogen  reaction,  49  ; 
oxydase  reaction,  50 ;  fatty  degeneration  of  the  blood-cells,  52  ;  vital  staining, 
52  ;  calcium  content  of  the  blood,  53. 

PAET   II 

The  Eoemed  Elements  of  the  Blood 

CHAPTER   VI 

The  Erythrocytes 

Colour,  size,  variations,  shape,  54  ;  effects  of  osmosis,  effect  of  heat,  pathological 
variations,  55  ;  structure,  polychromatophilia,  55  ;  rouleaux  formation,  60  ; 
numbers,  variations,  61  ;  nucleated  red  cells — significance  of  their  presence  in 
peripheral  blood,  62. 

CHAPTER   VII 

The  Leucocytes 

Numbers,  classification,  65  ;  leucocytes  not  found  in  normal  circulating  blood,  67  ; 
leucocyte  granules,  differential  counting  of  leucocytes,  69  ;  normal  propor- 
tions of  leucocytes,  functions  of  leucocytes,  70. 

CHAPTER   VIII 

Variations  in  the  Number  and  Proportions  op  Leucocytes 

Diminution,  leucopenia — physiological,  pathological,  73  ;  increase,  leucocytosis,  73  ; 
physiological — infancy,  pregnancy,  digestion,  the  moribund  state,  various,  74  ; 
pathological — neutrophil  leucocytosis,  75  ;  Arneth's  method,  76  ;  lymphocytosis 
— relative,  absolute,  77  ;  eosinophilia,  79  ;  basophilia,  80. 

CHAPTER    IX 

The  Blood-Plates  :  H^emoconia 
Blood-plates,  82  ;  hceinoconia,  84. 

CHAPTER    X 

The  Blood  in  Infancy,  Old  Age,  Etc. 

Infancy  and  childhood,  85  ;  old  age,  menstruation,  pregnancy  and  the  puerperium, 
86  ;  lactation,  87. 

CHAPTER   XI 
The  Blood  in  Certain  Animals 


CONTENTS  xi 

CHAPTER   XII 

Sources  of  the  Blood-Cells.     The  Bone-Marrow  and  its  Reactions 

Structure  of  bone-marrow,  fcctal,  yellow,  red,  95  ;  bone-marrow  reactions  and 
degenerations,  erythroblastic  reaction,  96  ;  megaloblastic  reaction,  leucoblastic 
reaction,  97 ;  fatty  degeneration,  fibroid  degeneration,  gelatinous  degenera- 
tion, 98. 

CHAPTER   XIII 
Development  op  the  Cells  of  the  Blood 
Leucocytes,  100  ;  erythrocytes,  111. 

PAET   III 

Diseases  of  the  Blood,  Bone-Marrow,  and  Lymphoid  Tissues — 
The  Bleeding  Diseases 

CHAPTER   XIV 
Pernicious  Anemia 

CHAPTER   XV 

Chlorosis 

CHAPTER   XVI 
Secondary  Anemia 
Acute  post-haemorrhagic  anaemia,  169  ;  simple  secondary  anaemia,  171. 

CHAPTER    XVII 
Aplastic  Anemia 

CHAPTER   XVIII 
Splenic  Anemia- — Phagocytic  Anemia 
Splenic  anaemia,  179  ;  Gaucher's  disease,  183  ;  phagocytic  anaemia,  184. 

CHAPTER   XIX 

HEMATOGENOUS   CYANOSIS — HEMOCHROMATOSIS— LlPEMIA 

Splenomegalic  polycythaemia,   186  ;  methaemoglobineemia,  189  ;  microbic  cyanosis, 
sulphhaemoglobinsemia,  190;  haemochromotosis,  lipaemia,  191. 

CHAPTRE   XX 
Leucocythemia 
Classification,  193  ;  lymphatic  leukaemia,  195. 


xii  CONTENTS 

CHAPTER  XXI 

LeucocytHjEMIA — (continued) 
Myelocythoemia,  209  ;  mixed  forms,  221  ;  chloroma,  222  ;  leucanaemia,  225. 

CHAPTER  XXII 

Lymphadenoma — Hodgkin's  Disease 

CHAPTER  XXIII 

Multiple  Myeloma 

CHAPTER  XXIV 

HAEMOPHILIA 

CHAPTER  XXV 

Purpura 

Sehonlein's  purpura,  Henoch's  purpura,  255  ;  purpura  simplex,  purpura  hsemor- 
rhagica,  256  ;   scurvy,  257  ;   infantile  scurvy,  260. 

CHAPTER  XXVI 

Paroxysmal  Hemoglobinuria 

CHAPTER  XXVII 

Blood  Diseases  of  Infancy  and  Childhood 

Pernicious  anaemia,  myelocythaemia,  265  ;  lymphatic  leukaemia,  secondary  anaemia, 
splenic  anaemia  of  infants,  266. 

CHAPTER  XXVIII 
Congenital  Family  Chol,emia 
Acholuric  jaundice,  269  ;  congenital  anaemia  with  obstructive  jaundice,  272. 

CHAPTER  XXIX 

Lymphatism 

PART  IV 

The  Blood  in  Special  Diseases 

CHAPTER  XXX 

Infectious  Diseases 

Introduction,  scarlet  fever,  278  ;  measles  and  rotheln,  mumps,  whooping-cough,  280  ; 
influenza,  diphtheria,  typhoid,  281  ;  typhus,  smallpox,  varicella,  283  ;  epidemic 
cerebro-spinal  meningitis,  cholera,  dysentery,  yellow  fever,  284  ;  dengue,  bubonic 
plague,  Malta  fever,  anthrax,  tetanus,  glanders,  hydrophobia,  beri-beri,  285  ; 
tuberculosis,  286  ;  syphilis,  288  ;  leprosy,  actinomycosis,  blastomycosis,  289. 


CONTENTS  xiii 

CHAPTER  XXXI 

Septic  and  Inflammatory  Conditions 

Introduction,  septicaemia,  septic  anaemia,  290  ;  appendicitis,  292  ;  salpingitis,  abscess, 
boil  and  carbuncle,  osteomyelitis,  293  ;  otitis  media,  gonorrhoea,  erysipelas, 
pleurisy,  pericarditis,  peritonitis,  294. 

CHAPTER  XXXII 

Malignant  Disease — Wounds  and  Fractures — Poisons 

Malignant  disease,  introduction,  296  ;  cancer,  297 ;  mediastinal  lymphosarcoma, 
significance  of  the  blood  changes  in  cancer,  297  ;  fractures,  wounds  and  aseptic 
operations,  298  ;  drugs,  poisons,  anaesthetics,  299. 

CHAPTER  XXXIII 

Diseases  op  the  Alimentary  System 

Alimentary  canal,  303 ;  intestinal  parasites,  305 ;  diseases  of  the  liver,  306 ;  pancreas, 
307  ;  peritonitis,  ascites,  308. 

CHAPTER  XXXIV 

Diseases  op  the  Ductless  Glands 

Diseases  of  the  spleen,  splenectomjr,  lymphatic  glands,  myxcedema,  308  ;  cretinism, 
exophthalmic  goitre,  acromegaly,  Addison's  disease,  310. 

CHAPTER  XXXV 

Diseases  op  the  Circulatory  System 

Simple  endocarditis,  malignant  endocarditis,  congenital  heart  disease,  acquired  heart 
disease,  312  ;  diseases  of  the  respiratory  system — adenoids,  bronchitis,  asthma, 
313  ;  emphysema,  bronchiectasis  and  lung  abscess,  phthisis,  pneumonia,  314. 

CHAPTER  XXXVI 

Diseases  op  the  Skin,  Genito-Urinary  and  Nervous  Systems — 
General  Diseases 

Diseases  of  the  skin,  318  ;  diseases  of  the  urinary  system,  319  ;  diseases  of  the 
reproductive  system,  320  ;  diseases  of  the  nervous  system,  321  ;  general 
diseases,  322. 


PAET  V 

Diseases  Due  to  Animal  Paeasites 

CHAPTER  XXXVII 

Malaria  or  Ague 

Etiology,  the  parasites,  325  ;  tertian  malaria,  332  ;  quartan  fever,  334 ;  subtertian 
(sestivo-autumnal)  fever,  334  ;  chronic  malaria,  latent  malaria,  336  ;  the  blood 
in  malaria,  337  ;  diagnosis,  341  ;  prognosis,  342  ;  treatment,  343. 


xiv  CONTENTS 

CHAPTER  XXXVIII 

Blackwater  Fever 

CHAPTER  XXXIX 

Kala-Azar 


Infantile  kala-azar,  354. 


CHAPTER  XL 
Trypanosomiasis 


Varieties  of  trypanosonies,  356  ;   human  trypanosomiasis — sleeping  sickness,  357 
Rliodesian  trypanosomiasis,  South  American  trypanosomiasis,  360. 

CHAPTER  XLI 

Diseases  Due  to  Spirochetes  in  the  Blood 
Relapsing  fever,  362  ;  tick  fever,  365. 

CHAPTER  XLII 

FlLARIASIS 

Filaria  Bancroft!,  367  ;  filaria  loa,  370  ;  filaria  perstans,  filaria  demarquayi,  371. 

CHAPTER  XL1II 

PlROPLASMATA,  ETC. 

Piroplasmata,  hsemogregarinida,  leucocytozoa,  372  ;  halteridium,  anaplasmata,  373. 

APPENDIX  A 

Splenectomy  in  Pernicious  Anaemia 

APPENDIX  B 

A  New  Staining  Method 


LIST   OF   ILLUSTRATIONS 


FIGURES   IN   TEXT 

Fli:. 

1.  Fibrin  Network  in  Normal  Conditions 

2.  Fibrin  Network  Increased     .... 

3.  The  Thoma  Hamrocytometer 

4.  The  Thoma  Slide       ..... 

5.  To  Show  Method  of  Applying  Cover-glass  . 

6.  Part  of  the  Thoma  Counting  Field  under  the  Microscope 

7.  Barker's  Counting  Chamber 

8.  Ruling  on  Barker's  Counting  Chamber 

9.  The  Thoma,  Zappert  and  Turk  Hamiocytometer  Ruling 

10.  Pipettes  of  Durham,  Hirschfeld  and  Pappenheim    . 

11.  Method  of  Using  Oliver's  Tintometer 

12.  Method  of  Counting  Leucocytes 

13.  Haldane's  Hsemoglobinometer 

14.  Von  Fleischl's  Hsemoglobinometer    . 

15.  Oliver's  Hsemometer .  .... 

16.  Camera  Tube  for  Use  with  Oliver's  H  osmometer      . 

17.  Viscosimeter  of  Denning  and  Watson 

18.  Beckmann's  Cryoscope  .... 

19.  Rei chert's  Universal  Condenser 

20.  21.  Scheme  of  Structure  of  Erythrocyte 

22.  Development  of  Leucocyte  Nucleus  . 

23.  Schematic   Curves  to   Illustrate  the   Onset   and    Course  of   Acute  and 

Chronic  Cases  of  Pernicious  Anaemia  . 

24.  Film  from  Case  of  Pernicious  Anosmia 

25.  Case  of  Hodgkin's  Disease     .... 

26.  Same  Case,  three  months  later 

27.  Life-History  of  the  Malaria  Parasite 

28.  Development  of  Trypanosome  and  Leishman-Donovan  Body 


PAGE 

2 


5 
5 
6 

7 
9 

9 
10 
12 
13 
14 
19 
20 
22 
23 
38 
45 
48 
58 
103 

123 
133 
231 
231 
327 
351 


COLOURED   PLATES 


I.  The  Glycogen  Reaction 
II.  Polychromatophilia 
III.  Types  of  Blood-Cells 


To  face  page  50 
56 
64 


XVI 


LIST   OF   ILLUSTEATIONS 


IV.  Normal  Red  Marrow  ....  To  face  page  96 

V.  Haematogenesis      .......,,         110 

VI.  Figure  1.  Aplastic  Red  Bone-Marrow  „         118 

Figure  2.  Marrow  from  Case  of  Pernicious  Anaemia       .  .  ,,118 

VII.  Blood  Film  from  Case  of  Pernicious  Anaemia      .  .  .  ,,         134 

VIII.  Blood  Film  from  Case  of  Chlorosis  .  .  .  .  ,,162 

IX.  Figure  1.  Marrow  from  Case  of  Acute  Lymphatic  Leukaemia    .  ,         196 

Figure  2.  Marrow  from  Case  of  Myelocythaemia  .  ■  ,,         196 

X.  Blood    Film    from    Case    of     Acute     Lymphatic     Leukaemia 

(Jenner's  Stain)  .......         204 

XI.  Blood    Film    from    Case    of     Acute     Lymphatic     Leukaemia 

(Leishman's  Stain)    .  .  .  .  .  „  '       206 

XII.  Blood  Film  from  Case  of  Myelocythsemia  (Jenner's  Stain)         .  ,,         214 

XIII.  Blood   Film   from  Case  of  Myelocythaemia  (Ehrlich's  Triple 

Stain)  ........         216 

XIV.  Blood  Film  from  Case  of  Septic  Anaemia  „         292 
XV.  Blood  Parasites     ........        324 

XVI.  Blood  Film  from  Case  of  Malaria  .  .  .  .  „         340 


THE   BLOOD: 

A    GUIDE    TO    ITS    EXAMINATION    AND    TO    THE 
DIAGNOSIS  AND   TREATMENT   OF  ITS   DISEASES 

PART    I 
METHODS   OF  EXAMINING  THE   BLOOD 

CHAPTER  I 

EXAMINATION   OF   FRESH   SPECIMENS:   ENUMERATION 
OF   RED    CORPUSCLES 

Withdrawal  of  Samples  of  Blood. — For  ordinary  examinations  blood 
is  most  conveniently  obtained  from  the  lobule  of  the  ear  and  from  its 
edge  rather  than  its  flat  surface.     The  skin  is  less  sensitive,  and  the 
epidermis  is  thinner  than  that  of  the  finger.     A  rub  with  a  cloth  is 
all  that  is  required  in  the  way  of   cleaning  the  skin,  and  the  slight 
hyperemia   thus   produced   causes  a  freer  flow  of   blood.     Antiseptic 
precautions  are  unnecessary,  and  cleaning  with  ether  should  be  avoided, 
as  it  tends  to  cause  a  local  leucocytosis.     If   the  skin  be  very  dirty 
water  or  soap   and  water   may  be  used.      Care  should  be  taken  that 
blood  be  not  drawn  from  a  dropsical  part,  as  in  that  case  it  is  diluted 
by  water  from  the  tissues,  nor  from  a  cyanosed'  part,  as  it  is  then 
always  concentrated.     For  this  reason  also  the  part  should  always  be 
warm.     The  puncture  should  be  made  with  an  instrument  which  has 
cutting  edges.     Special  instruments  are  supplied  for  the  purpose,  but 
a  surgical  needle  or  a  fine  trocar  serves  admirably ;  best  of  all  is  a  von 
Graefe's   cataract   knife,  sharpened  to  a  point   rather   than   an   edge. 
Sterilisation  of  the  knife  is  unnecessary,  provided  that  it  is  clean  and 
bright  and  used  for  no  other  purpose.     It  may  be  dipped  in  absolute 
alcohol   occasionally.      A  sharp,  tapping  action  should  be  employed, 
and  not  a  slow,  boring  movement,  which  is  much  more  painful.     Slight 
pressure  may  be  employed  to  start  the  flow  of  blood,  and  the  first  few 
drops,  which  carry  with  them  skin  contamination,  should  be  wiped  off. 

1 


2  EXAMINATION   OF   FEESH   SPECIMENS 

Only  blood  which  escapes  without   pressure   and   fairly  freely  should 
be  used. 

Caution. — In  cases  of  haemophilia  and  in  some  cases  of  leukaemia  and 
pernicious  anaemia  bleeding  from  a  puncture  may  not  readily  stop.  In 
such  cases  it  is  preferable  to  take  blood  from  the  finger,  where,  if 
necessary,  a  bandage  can  be  readily  applied. 

The  beginner  may  readily  obtain  samples  of  his  own  blood  for  examina- 
tion (wben  accuracy  is  not  an  important  consideration)  by  winding  a  hand- 
kerchief round  the  proximal   phalanx  of  the  thumb  and  then  flexing  the 


Fig.  1. — Fibrin  Network  in  Normal  Conditions. 


phalangeal  joint.  The  congested  skin  over  the  back  of  the  terminal  phalanx 
after  a  slight  puncture  yields  a  copious  supply  of  blood  which  stops  on 
extending  the  thumb  and  starts  again  on  flexion,  and  thus  successive  drops 
may  be  obtained  without  a  corresponding  number  of  punctures. 

Examination  of  Fresh  Blood. — As  blood  exudes  after  a  puncture 
its  colour  and  fluidity  should  be  noted.  For  microscopic  examination  a 
drop  of  blood  is  touched  with  a  cover-slip,  which  is  then  placed  on 
a  slide.  Practically  all  the  information  that  this  method  yields  is 
better  given  by  stained  films. 

Rouleaux  formation1  may  be  noted.  It  is  deficient  when  there  is 
deformity  or  alteration  in  size  of  the  red  corpuscles. 

The  shape  and  size  of  the  cells  are  seen  in  this  way  with  the  minimum 
of  artificial  distortion. 

1  See  Wiltshire,  Journ.  of  Path,  and  Bad.,  xvii.  1913. 


EXAMINATION   OF  FBESH   SPECIMENS  3 

The  projjortions  of  cells  and  their  characters  are  better  made  out  in 
stained  specimens. 

The  Fibrin  Network. — The  density  of  the  fibrin  network  can  be 
studied  in  fresh  specimens  which  have  stood  for  fifteen  minutes. 
Only  a  small  amount  of  light  should  be  used.  The  fibrin  threads 
will  be  seen  forming  a  network,  and  in  many  cases  radiating  from 
a  little  clump  of  blood-plates. 

The  fibrin  network  is  increased  in  pneumonia,  acute  rheumatism 


Fig.  2. — Fibrin  Network  Increased. 

and   inflammatory  conditions.     It   is   unaltered  in  malignant   disease 
and  markedly  diminished  in  pernicious  aneemia. 

It  is  important  in  clinical  work  that  samples  of  blood  should  be 
obtained  with  the  least  inconvenience  to  the  patient.  One  puncture 
should  be  sufficient  for  an  ordinary  routine  examination.  The  procedure 
will  be  stated  after  discussion  of  the  different  methods  in  detail. 

Enumeration  of  the  Red  Corpuscles. — The  number  of  red  cells  in 
a  unit  of  blood  is  too  great  to  count,  and  therefore  the  sample  must 
be  diluted.  The  diluting  fluid  must  fulfil  two  conditions — it  must 
prevent  coagulation,  and  it  must  not  affect  the  red  cells  by  osmosis, 
i.e.  it  must  be  isotonic.     Many  formulae  have  been  suggested. 

1.  As  useful  as  any  is  ordinary  physiological  salt  solution,  sodium 
chloride,  0'9  per  cent.  It  has  the  advantage  that  almost  any  of  the 
dye  stuffs  may  be  dissolved  in  it. 


EXAMINATION   OF  FRESH   SPECIMENS 


2.  Gowers'  solution — 

Sodium  sulphate 

Acetic  acid   .... 

Distilled  water 

3.  Hayem's  solution — 

Perchloride  of  mercury 
Sodium  sulphate 
Sodium  chloride 
Distilled  water 

This  solution  is  deservedly  the  one  most  commonly  used.  It  pre- 
serves well  both  the  shape  and  colour  of  the  red  corpuscles,  It  keeps 
well,  though  a  deposit  forms  after  a  time.  This  can  be  filtered  off 
without  spoiling  the  solution. 

4.  Toisson's  solution — 


104  grs. 

1  drm. 

6  ozs. 

05  grm 

5  grms. 

1  grm. 

200  c.c. 

Sodium  sulphate 

8  grms. 

Sodium  chloride 

1  grm. 

Methyl  violet  5  B     . 

0-025  grm 

Glycerine  (neut.) 

30  c.c. 

Distilled  water 

.      160  c.c. 

This  solution  stains  the  nuclei  of  the  leucocytes  while  conserving 
the  red  cells.  Some  of  the  latter,  however,  when  pale,  are  not  well 
seen,  and  the  count  is  therefore  apt  to  be  too  low.  The  methyl  violet 
sometimes  precipitates,  and  there  is  no  great  practical  advantage  in 
the  staining  of  the  leucocyte  nuclei. 

The  Thoma-Zeiss  Hazmocytonieter, — This  instrument,  or  one  of  its 
modifications,  is  in  common  use,  and  is  very  convenient.  It  is  designed 
to  indicate  the  number  of  corpuscles  in  a  cubic  millimetre  of  blood. 
As  supplied  it  consists  of  two  pipettes  and  a  counting  chamber.  One 
pipette  has  a  fine  bore  and  a  large  bulb  by  which  a  sample  of  blood 
may  be  diluted  either  100  or  200  times,  the  other  has  a  wide  bore 
and  a  small  bulb  by  means  of  which  blood  may  be  diluted  either  ten 
or  twenty  times.  The  latter  is  specially  intended  -for  the  enumeration 
of  white  cells. 

In  the  case  of  the  red  cell  pipette,  if  blood  be  taken  up  to  the 
mark  0'5,  and  diluting  fluid  up  to  the  mark  101,  the  dilution  will  be 
1  in  200;  if  blood  be  taken  up  to  the  mark  1,  and  diluting  fluid  to 
the  mark  101,  the  dilution  will  be  1  in  100.  The  most  convenient 
dilution  is  1  in  200,  unless  the  blood  be  very  poor  in  corpuscles,  when 
1  in  100  should  be  used. 


EXAMINATION   OF   FEESH   SPECIMENS  5 

The  counting  chamber  consists  of  a  round  glass  table  surrounded  by 
a  trench,  and  then  by  a  square  glass  plate  CM  mm.  higher  than* the 
counting  chamber  (Fig.  4).  The  central  area  of  the  counting  table  is 
divided  by  microscopic  ruling  into  sixteen  sets  of  sixteen  squares. 
Each  square  is  j^  mm.  in  area.     The  squares  round  each  set  of  sixteen 


Fig.  3. — The  Thoma  H^emocytometer. 

are  bisected  for  the  sake  of  clearness  (Fig.  6).  A  cover-slip  ground 
flat  is  supplied  with  the  instrument,  and  when  this  is  applied  the  depth 
of  the  counting  chamber  is  ^  mm. 

Procedure. — The  diluting  fluid  to  be  used  should  be  at  hand  in  a 
bottle,  or  a  little  may  be  poured  out  into  a  watch-glass.  The  ear 
is  punctured,  and  the  first  two  drops  of  blood  are  wiped  off.     As  soon 


Fig.  4.— Section  of  Counting  Chamber. 

(Tlie  cover-slip  is  raised  for  clearness.) 

as  the  next  drop  of  blood  becomes  as  big  as  a  split  pea  some  of  it  is 
sucked  into  the  pipette  as  far  as  the  mark  0*5.  A  little  practice  is 
requisite  in  order  that  this  may  be  done  accurately  and  smartly,  and 
in  certain  conditions  where  coagulation  time  is  short  rapidity  of 
manipulation  is  necessary.  The  point  of  the  pipette  is  more  easily 
held  steady  if  the  little  finger  rests  on  the  patient's  cheek.  The  rubber 
tube  attached  to  the  pipette  should  be  long  enough  to  allow  the 
operator  to  look  at  right  angles  to  the  top  of  the  advancing  column  of 
blood  so  as  to  note  exactly  the  point  it  has  reached.     If  too  much  blood 


6  EXAMINATION  OF  FEESH   SPECIMENS 

be  taken  up  it  is  not  easy  to  blow  out  just  the  amount  of  the  excess, 
but  frequently  a  small  excess  may  be  got  rid  of  by  merely  stroking  the 
point  of  the  pipette  with  the  finger.  If  the  excess  be  considerable  the 
blood  should  be  drawn  up  to  the  mark  1.  As  soon  as  the  blood  stands 
at  the  proper  mark  any  blood  adhering  to  the  outside  of  the  pipette 
should  be  wiped  off  and  the  point  of  the  pipette  plunged  into  the 
diluting  fluid,  which  is  sucked  up,  while  the  pipette  is  gently  rolled  to 
ensure  thorough  mixing,  until  the  mixture  reaches  the  point  101.  If 
the  mixture  slightly  passes  this  point  it  does  not  greatly  matter.  It 
is  of  much  greater  importance  that  the  0*5  mark  should  be  reached 
exactly.  The  pipette  is  now  held  by  placing  the  finger  and  thumb  at 
the  ends  and  shaken  vigorously,  or  it  may  be  held  in  the  horizontal 
position  and  rolled  between  the  finger  and  thumb  for  half  a  minute,  so 
that  the  blood  is  thoroughly  mixed  with  the  diluting  fluid.  The  mixing 
is  facilitated  by  means  of  a  glass  bead  contained  in  the  bulb.     As  the 


Fig.  5. — To  Show  Method  of  Applying  Cover-glass. 

long  limb  of  the  pipette  contains  diluting  fluid  only,  nearly  half  of  the 
contents  of  the  bulb  should  be  blown  out  in  order  that  a  sample  from 
the  bulb  may  be  obtained.  A  drop  of  the  diluted  blood  is  now  blown 
out  or  allowed  to  drop  out  upon  the  centre  of  the  counting  chamber. 
This  drop  should  be  large  enough  to  cover  at  least  three-quarters  of 
the  central  area  without  overflowing  into  the  surrounding  trench  when 
the  cover-glass  is  applied.  In  this  matter  again  practice  is  requisite. 
The  cover-glass  supplied  is  ground  flat,  and  care  should  be  taken  that 
its  thickness  does  not  exceed  the  focal  distance  of  the  objective  to  be 
employed. 

A  i-inch  lens  is  very  suitable.  The  counting  chamber  and  cover- 
glass  should  be  absolutely  clean  and  should  fit  accurately,  so  that  when 
applied  to  each  other  Newton's  colour  rings  should  be  visible.  They 
are  more  easily  obtained  with  some  instruments  than  others. 

The  application  of  the  cover-glass  always  presents  difficulties  to 
beginners.  It  must  be  done  quickly,  for  the  corpuscles  at  once  begin 
to  settle  on  the  ruled  area,  and  as  the  drop  of  diluted  blood  is  convex, 
this  rain  of  corpuscles  is  greatest  at  the  centre,  so  that  delay  causes 
uneven  distribution.     The  cover-glass  should  be  lowered  obliquely,  one 


EXAMINATION   OF  FEESH   SPECIMENS  7 

side  being  allowed  to  rest  on  the  outer  square  and  held  steady  with  the 
fingers  of  the  left  hand,  the  other  lowered  gradually  on  to  the  drop,  at 
first  with  a  needle,  but  as  practice  makes  it  easier,  with  the  fingers 
of  the  right  hand.  Another  method  which  may  be  of  service  to  the 
beginner  is  to  fix  the  cover-slip  against  the  edge  of  the  outer  square 
with  the  left  forefinger  and  then  push  it  down  with  the  right,  using 
the  edge  of  the  square  as  a  fulcrum  (Fig.  5).  The  counting  slide  should 
then  be  held  level  with  the  eye  and  between  it  and  a  light  source  to 


■— H 

Fig.  6. — Part  op  the  Counting  Field  under  the  Microscope. 

make  sure  that  Newton's  rings  have  appeared.  It  should  next  be 
examined  with  the  low  power  of  the  microscope.  If  air-bubbles  be 
present  the  preparation  is  useless,  and  the  slide  and  cover-glass  must 
be  cleaned  and  a  fresh  preparation  made.  The  same  must  be  done  if 
the  corpuscles  are  not  evenly  distributed,  right  to  the  edge  of  the  drop. 
The  most  usual  error  is  that  they  are  too  thickly  crowded  over  the 
centre  of  the  ruled  space.  It  is  impossible  to  lay  too  much  stress  on 
even  distribution,  for  upon  it  the  accuracy  of  the  count  hinges  entirely. 
The  figures  quoted  in  the  annexed  example  give  about  the  maximum 
range  of  allowable  divergence.  If  the  range  is  greater  a  fresh  prepara- 
tion  should    be   made  after   the   fluid   in   the   bulb   has   been   again 


8  EXAMINATION   OF  FBESH   SPECIMENS 

thoroughly  shaken   up,  and   that  which   has  been  lying  in  the  long 
limb  of  the  pipette  expelled. 

Turk ]  has  suggested  that  a  very  small  drop  of  the  diluting  fluid  should 
be  placed  under  two  opposite  corners  of  the  cover-glass.  Although  this 
procedure  might  be  objected  to  on  theoretical  grounds,  there  is  no  doubt 
that  the  capillary  attraction  of  the  fluid  gives  good  contact,  and  the  colour 
rings  are  more  readily  brought  out. 

The  number  of  corpuscles  in  a  large  number  of  squares  must  now 
be  counted  in  order  to  find  the  average  number  per  square.  In  count- 
ing the  corpuscles  in  a  set  of  sixteen  squares  all  those  on  interior  lines 
must  be  included,  but  only  half  of  those  on  the  lines  bounding  the  half 
squares  must  be  counted.  This  may  be  carried  out  by  counting  all  the 
boundary  line  cells  on  the  left  and  top,  and  omitting  all  those  on  the 
right  and  foot.  It  is  convenient  to  count  the  number  of  cells  in  five 
sets  of  sixteen  squares,  i.e.  in  a  total  number  of  eighty  squares  and 
divide  that  number  by  80  to  find  the  average  per  square.  To  find  the 
number  per  cubic  millimetre  we  must  multiply  this  average  number  by 
400  (the  area  of  each  square  being  —^  mm.)  and  by  10  (the  depth  of 
each  square  being  TV  mm.)  and  by  200  (the  extent  of  the  dilution). 
Suppose  the  numbers  counted  were  as  follows : — 


In  the  first  set  of  16 

squares 

108 

,,      second 

5) 

j> 

96 

,,      third 

JJ 

j> 

98 

,,      fourth 

>) 

)> 

120 

„      fifth 

In 

80 

squares 

121 

543 

543  x 

400 

x 10  x  200 

_fi.4 

30.000  nftr  n.mm. 

SO  -,-~,v  —  r~  ~™. 

It  may  be  noted  that  when  the  number  of  corpuscles  in  eighty 
small  squares  is  counted,  the  addition  of  four  cyphers  at  once  gives 
the  number  per  cubic  millimetre,  when  the  dilution  is  1  in  200. 

In  making  the  enumeration  a  rather  small  diaphragm  should  be 
used,  and  if  a  substage  condenser  is  employed,  it  should  be  a  little 
lower  than  the  position  for  examining  stained  specimens. 

It  is  convenient   to  arrange   the   combination  of   objective,  tube- 
length,  and  number  of  eye-piece  so  that  the  visible  field  just  exceeds 
the  sixteen  small  squares  which  are  being  counted. 
1  Vorlemngen  iiber  klinische  Iliimatologie,  1904. 


EXAMINATION   OF   FRESH   SPECIMENS 


It  is  only  in  hospital  and  consulting-room  that  the  corpuscles  can 
conveniently  be  counted  immediately  the  pipette  is  filled.  When  this 
is  done  at  a  distance  from  a  microscope  a  rubber  band  of  appropriate 
length  and  fair  thickness  is  slipped  over  the  ends  of  the  pipette.  This 
seals  the  openings,  and  the  pipette  can  then  be  replaced  in  the  box  and 

\ 


Fig.  7. — Burker's  Counting  Chamber  with  Cover-slip  Applied. 

(The  arrows  indicate  where  the  drop  of  diluted  blood  is  to  be  placed.) 

taken  home.  Care  should  be  taken  that  the  pipettes  are  kept  approxi- 
mately level  in  transit — the  box  should  be  carried  at  the  bottom  of 
a  bag  rather  than  in  the  coat-tail  pocket — lest  a  proportion  of  the 
corpuscles  escape  into  one  or  other  limb  of  the  pipette.  Presumably 
the  pipettes  might  be  left  indefinitely  and  the  counting  done  at  any 


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Fig.  8.— Ruling  on  Burker's  Counting  Chamber. 

future  time,  but  the  corpuscles  are  apt  to  stick  together.  "We  have 
obtained  an  even  distribution  at  the  end  of  three  days,  but  do  not 
recommend  so  long  a  delay.  The  longer  the  pipette  has  been  allowed 
to  lie  the  more  thorough  must  be  the  shaking  and  rolling  before  the 
count  is  carried  out. 

After  use  the  instruments  must  be  very  thoroughly  cleaned  (see 
Chap.  III.). 


10 


EXAMINATION   OF  FEESH   SPECIMENS 


Burner's  Hccmocytometer} — This  is  an  important  modification  of  the 
Thoma-Zeiss  instrument. 

The  counting  chamber  is  bisected  by  a  transverse  channel.  On 
each  side  of  the  counting  plate  there  is  a  rectangular  piece  of  glass 
arranged  to  leave  a  gap  between  its  inside  edge  and  the  side  of  the 
counting  table.  The  side  plates  are  0*1  mm.  higher  than  the  counting 
plate.  The  counting  plate  has  on  each  side  of  the  central  division  the 
ruling  shown  in  Fig.  8  over  an  area  of  3  x  3  mm.  Each  small  square 
corresponds  to  one  square  of  the  Thoma-Zeiss  ruling,  and  each  large 
square  corresponds  to  sixteen  squares. 

In  another  form  of  the  instrument  there  is  a  simple  stage  micro- 
meter and  a  number  of  square  stops  of  different  size  to  fit  into  the  eye- 
piece.    The  size  of  the  eye-piece  aperture  is  determined  by  means  of 


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Fig.  9. — The  Thoma,  Zappert,  and  Turk  H^emocytometer  Ruling. 

the  stage  micrometer  (the  magnification  being  adjusted  by  the  use  of  the 
draw-tube)  and  then  the  corpuscles  are  counted  in  a  series  of  micro- 
scopic fields  of  known  extent  and  of  course  0*1  mm.  depth. 

We  prefer  the  first  type  of  instrument,  and  instead  of  Burker's 
ruling  we  use  that  of  Turk  (Fig.  9). 

To  use  this  counter  the  cover-slip  is  first  applied.  A  drop  of  diluted 
blood  is  then  placed  on  the  counting  table  at  the  edge  of  the  cover-slip, 
and  just  the  right  quantity  finds  its  way  into  one  side  of  the  counting 
plate  by  capillary  action. 

The  advantages  claimed  for  this  instrument  are — 1.  That  all  difficulty 
in  the  way  of  filling  the  counting  chamber  with  the  right  amount  of 
diluted  blood  and  of  applying  the  cover-glass  is  eliminated. 

2.  That  there  is  no  time  for  deposition  of  corpuscles  before  the  drop  of 
diluted  blood  has  spread  out,  and  that  distribution  is  therefore  more  even. 

3.  The  double  counting  chamber  permits  of  a  check  enumeration 
without  disturbing  the  cover-glass. 

1  Pfliiger's  Archiv,  cvii.  1905,  426. 


EXAMINATION   OF  FRESH   SPECIMENS  11 

Counting  Chambers  of  Zappert  and  Tiirli. — Many  modifications  of 
the  Thoma-Zeiss  ruling  have  been  introduced  with  the  idea  of  affording 
a  larger  counting  area  than  is  provided  by  the  Thoma-Zeiss  instrument. 
This  is  specially  desirable  when  leucocytes  are  being  counted. 

The  following  may  be  taken  as  types  of  a  very  large  number 1 : — 

Zappert's  Counting  Chamber. — The  central  area  corresponds  to  that 
of  the  Thoma  instrument,  but  the  peripheral  area  is  ruled  into  larger 
squares.  The  whole  area  of  3x3  mm.  is  divided  by  heavy  cross  ruling 
into  nine  large  squares,  each  equal  in  area  to  the  central  area  of  400 
small  squares.  The  whole  ruled  area  therefore  corresponds  to  3600 
small  squares.  The  peripheral  squares  are  for  convenience  divided 
into  four,  each  quarter  corresponding  to  100  small  squares. 

Turk's  Counting  Chamber. — This  is  similar  to  the  Zappert  instru- 
ment, but  the  large  peripheral  squares  are  divided  into  areas  corre- 
sponding to  sixteen  small  squares  and  each  of  these  areas  is  in  turn 
surrounded  by  lines  corresponding  to  those  which  enclose  the  bisected 
squares  of  the  central  area. 

Gowers'  Hcemocytometer. —  This  instrument  consists  of  a  pipette 
'  graduated  to  measure  5  c.mm.  of  blood,  a  second  pipette  to  measure 
995  c.mm.  of  diluting  fluid,  a  mixing  chamber  with  stirrer,  and  a  count- 
ing chamber.  The  instrument  is  not  so  convenient  as  the  Thoma 
hcemocytometer.  The  squares  on  the  counting  chamber  are  yjy  mm.  in 
area,  and  the  depth  when  the  cover-slip  is  applied  is  ^  mm.  The 
number  of  corpuscles  in  ten  squares  multiplied  by  10,000  gives  the 
number  in  a  cubic  millimetre  of  undiluted  blood. 

Hcemocytometers  of  Hayem  and  Malassez. — These  instruments  are 
now  almost  entirely  replaced  by  the  foregoing. 

Durham's  Pipette.2 — One  of  the  short  thick-walled  capillary  tubes 
introduced  by  Oliver,  having  a  capacity  of  5  or  10  c.mm.,  is  fixed  by 
means  of  a  cork  in  one  end  of  a  glass  pipette.  The  other  end  of  the 
pipette  is  fitted  with  a  rubber  cap,  which  has  a  side  perforation.  A 
separate  measure  for  diluting  fluid  is  required,  and  a  small  test-tube 
containing  a  glass  bead  is  used  as  a  mixing  chamber.  When  brought 
into  contact  with  a  drop  of  blood  the  capillary  tube  fills  itself.  By 
compressing  the  rubber  nipple  in  such  a  way  that  the  perforation  is 
closed  the  blood  is  expelled  into  the  measured  diluting  fluid.  The 
process  may  be  repeated  with  the  diluted  blood  to  ensure  complete 
washing  out  of  the  blood  from  the  capillary  tube. 

1  Illustrated  examples  will  be  found  in  Leitz's  catalogue. 

2  Edin.  Med.  Jouni.,  1897. 


12 


EXAMINATION   OF   FKESH   SPECIMENS 


Hirsclifdd's  Pipette} — This  instrument  ensures  great  accuracy  of 
measurement,  but  is  difficult  to  clean,  and  entails  the  use  of  a  separate 
mixing  chamber.  Diluting  fluid  is  first  sucked  up  into  the  bulb.  The 
stop-cock  is  then  reversed  and  the  excess  is  blown  out.  Blood  is  now 
sucked  up,  and  by  again  reversing  the  stop-cock  blood  and  diluent  can 
be  blown  out  into  a  mixing  chamber. 

Pappenheim's  Pipette.2 — In  this  instrument  the  rubber  tube  of  the 
Thoma-Zeiss  pipette  is  replaced  by  a  closely-fitting  glass  cap.  By  a 
syringe  action  suction  can  be  exerted  on  the  blood  and  diluting  fluid. 


f 


Fig.  10. — Pipettes  of  Durham,  Hirschfeld,  and  Pappenheim. 

Oliver's  Tintometer. — This  instrument  does  away  with  the  necessity 
for  microscopic  work,  and  affords  a  rapid  means  of  estimating  the 
number  of  red  corpuscles.  It  consists  of  a  rectangular  test-tube,  whose 
mouth  measures  15  mm.  by  5  mm.,  a  self-filling  capillary  tube  of  10  c.mm. 
capacity,  and  a  rubber-capped  pipette  with  about  a  quarter  inch  of 
rubber  tubing  at  its  end.  The  test-tube  is  calibrated  by  placing  in  it 
10  c.mm.  of  normal  blood  and  diluting  it  with  Hayem's  solution.  Day- 
light must  be  excluded,  and  a  candle  at  a  distance  of  about  4  ft.  is 
looked  at  through  the  narrow  sides  of  the  tube.  The  dilution  is  con- 
tinued until  a  bright  horizontal  line  is  seen  on  the  glass.  This  line  is 
made  up  of  numerous  minute  images  of  the  candle  produced  by  the 

1  Folia  Hcematologica,  xii.  ;  Centralb.,  1911,  245. 

2  Deutsche  meal.  Wochenschr.,  1912,  2067. 


EXAMINATION   OF   FRESH   SPECIMENS 


13 


longitudinal  striation  of  the  glass.  This  line  is  marked  100,  and 
corresponds  to  a  blood-count  of  5,000,000  per  c.mm. 

To  use  the  instrument  a  small  quantity  of  Hayem's  solution  is  first 
dropped  into  the  test-tube.  The  capillary  tube  is  now  filled  by  holding 
its  point  horizontally  in  a  drop  of  blood.  Its  point  is  wiped.  By  means 
of  the  capped  pipette,  which  is  fitted  to  the  more  pointed  end  of  the 
capillary  tube  by  the  rubber  tubing,  the  blood  is  expelled  into  the 
test-tube. 

Hayem's    solution   is   now  added   until  the  bright  horizontal  line 


Fig.  11. — Method  of  Using  Oliver's  Tintometer. 

appears,  and  the  percentage  of  red  cells  is  read  off  at  the  level  of  this 
line.  This  instrument  is  accurate  for  blood  not  too  markedly  abnormal. 
It  requires  a  dark  room,  and  is  perhaps  more  suited  for  the  laboratory 
than  for  clinical  work. 

The  Hematocrit. — This  instrument  has  not  found  a  great  deal  of 
favour.  It  consists  of  a  graduated  capillary  tube,  which  is  filled  with 
blood  and  then  centrifuged.  The  height  of  the  column  of  the  corpuscles 
gives  an  indication  of  their  number.  Alterations  in  shape  or  elasticity 
of  the  corpuscles  are  factors  which  may  influence  the  results  of  this 
procedure.  In  health  the  proportion  of  plasma  to  volume  of  corpuscles 
is  roughly  two  to  one.  Capps l  uses  the  term  "  volume  index  "  to  express 
the  relationship  between  the  volume  of  the  corpuscles  and  their  number. 
The  volume  expressed  as  a  percentage  of  the  volume  in  health  is 
divided  by  the  number  of  red  cells  as  counted  by  the  Thoma  hsemo- 
cytometer,  and  expressed  as  a  percentage  of  5,000,000. 

The  index  is  high  in  pernicious  anaemia,  practically  normal  in  cases 
of  moderate  secondary  ansemia,  and  low  in  severe  secondary  anaemia. 
1  J  own.  of  Med.  Research,  1903. 


CHAPTER  II 
ENUMERATION   OF  LEUCOCYTES  AND  BLOOD-PLATES 

Enumeration  of  Leucocytes. — The  Thoma  hfemocytometer  or  a  modifi- 
cation is  commonly  used.  The  pipette  with  a  wide  bore  and  small  bulb 
is  employed.     Blood  is  sucked  up  to  the  mark  0-5  and  diluting  fluid  up 


Z  < 

3  - 

4  - 

5  - 
6- 
7- 
8- 


Fig.  12. — Method  of  Counting  Leucocytes. 

to  the  mark  11,  giving  a  dilution  of  1  in  20.  If  blood  be  sucked  up  to 
the  mark  1  the  dilution  will  be  1  in  10.  Owing  to  the  wide  bore  of 
the  pipette  it  must  be  kept  horizontal  to  prevent  fluid  escaping.  The 
diluting  fluid  should  "lake"  the  red  corpuscles  and  show  up  the  white 
cells.  One  which  fulfils  these  requirements  is  1  c.c.  of  glacial  acetic 
acid  in  100  c.c.  of  distilled  water  to  which  enough  methyl  green  has 
been  added  to  colour  the  solution  a  fairly  deep  green.  The  acetic  acid 
renders  the  nuclei  sharp,  the  methyl  green  tints  them  faintly.     The 

14 


ENUMEEATION"   OF   LEUCOCYTES   AND  BLOOD-PLATES     15 

procedure  is  exactly  the  same  as  in  counting  the  red  cells  and  the  same 
counting  chamber  is  used.  As  their  numbers  are  small,  the  leucocytes 
in  a  large  number  of  squares  must  be  counted  in  order  to  obtain  an 
average.  It  is  advisable  to  count  the  white  cells  not  only  in  the  whole 
sixteen  sets  of  sixteen  squares  but  also  in  the  divided  squares  surround- 
ing the  sets.  The  total  number  of  squares  is  then  400.  In  making 
the  enumeration  a  mechanical  stage  is  a  great  advantage. 

We  make  the  count  by  beginning  with  the  square  at  the  top  left- 
hand  corner  as  it  appears  under  the  microscope  and  place  the  slide  so 
that  a  row  of  bisected  squares  is  at  the  top.  Moving  the  field  from  left 
to  right  we  count  all  the  leucocytes  in  the  two  top  rows  of  squares, 
i.e.  the  top  row  of  half  squares  and  the  row  of  whole  squares  below  it. 
Moving  the  field  up  we  then  count  from  right  to  left  all  the  leucocytes 
in  the  next  three  rows.  The  number  may  be  jotted  down  and  then  the 
process  is  repeated  three  times.  Suppose  the  dilution  has  been  1  in  10 
and  the  actual  number  counted  was  70.  That  number  divided  by  400 
gives  us  the  average  number  per  square. 

70  x  400  x  10  x  10     ,_.__ 

77:7; =  7000  per  c.mm. 

400  l 

ISTote  that  (when  the  dilution  is  1  in  10)  the  number  counted 
multiplied  by  100  at  once  gives  the  number  per  cubic  millimetre. 

It  is,  of  course,  quite  possible  to  count  both  red  and  white  cells  at  the 
same  time  by  using  the  same  pipette.  This  plan  is  useful  in  counting  the 
leucocytes  of  animals  with  nucleated  red  cells.  The  red  cell  pipette  is  used, 
and  a  diluting  fluid  which  conserves  the  red  cells  and  shows  up  the  white 
cells  is  necessary.  For  this  purpose  Toisson's  fluid  or  physiological  salt 
solution  coloured  with  methylene  blue  may  be  used.  The  drawback  to  this 
procedure  is  that  the  large  dilution  does  not  give  a  sufficient  number  of  white 
cells  to  yield  a  satisfactory  average.  This  disadvantage  may  be  minimised 
by  using  a  counting  chamber  such  as  that  of  Zappert  or  Turk  (Fig.  9). 

Some  practical  points  in  connection  with  the  counting  of  white  cells 
may  be  noted.  Unless  one  is  dealing  with  a  leucocythtemia  the  1  in 
10  dilution  should  always  be  used.  The  more  leucocytes  are  counted 
the  more  nearly  accurate  is  the  result.  Beginners  should  always  repeat 
the  count  with  a  second  drop,  but  with  greater  practice  this  becomes 
unnecessary.  The  settling  of  the  whites  on  the  ruled  space  takes  a 
much  longer  time  than  that  of  the  reds,  and  counting  should  not  be 
attempted  till  it  is  complete,  lest  some  corpuscles  remain  out  of  focus. 
If  comparative  counts  are  to  be  made  on  successive  days,  it  is  important 


16     ENUMERATION   OF  LEUCOCYTES   AND   BLOOD-PLATES 

that  this  should  be  done  as  nearly  as  possible  at  the  same  hour  and 
under  the  same  conditions  as  regards  rest  and  exercise,  length  of 
time  after  a  meal,  etc.  The  "  standard "  time  is  in  the  middle  of  the 
forenoon. 

The  Method  of  Measured  Fields. — In  this  method  the  leucocytes  are 
counted  not  in  squares  but  in  circular  areas  measured  by  the  diameter 
of  the  microscopic  field.  The  depth,  TV  mm.,  is  determined  by  the 
Thoma  counting  chamber.  Many  different  methods  have  been  sug- 
gested. One  of  the  simplest  is  that  of  Turton.1  The  cubic  capacity  of 
each  quantity  of  fluid  counted  is  -^  com.  The  diameter  required  to 
give  this  is  practically  7-|  squares  of  the  Thoma-Zeiss  chamber.  As 
every  fifth  square  is  divided,  all  that  is  necessary  is  to  take  a  quarter  of 
a  half  square  along  with  seven  whole  squares  to  get  the  field  required. 
Using  a  ^-inch  objective  it  is  easy  to  arrange. such  a  field  by  moving 
the  draw-tube.  The  tube-length  is  noted  and  the  field  can  then  be 
immediately  arranged  at  any  time.  Twenty  fields  may  be  counted. 
Suppose  the  dilution  to  be  1  in  20  and  70  leucocytes  are  seen.  The 
average  number  in  t^q  c.mm.  will  be  70  divided  by  20. 
70  x  100  x  20 


20 


=  7000  per  c.mm. 


Note  that  the  addition  of  two  cyphers  to  the  number  in  twenty 
fields  at  once  gives  the  number  per  cubic  millimetre. 

Barker's  Method. — Biirker's  hremocytometer  is  used  as  described 
on  p.  10. 

Strong  and  Seligmctn's  Method.2 — In  this  method  a  counting  chamber 
is  dispensed  with.  Five  c.mm.  of  blood  are  mixed  with  495  c.mm.  of  the 
following  solution : — 

Sodium  chloride  ....         0-75  grm. 

Methyl  violet  .  .  .  .         0-012  grm. 

Formaline  .  .  .  .1-5  o.cm. 

Distilled  water  .  .  .  .     to  100  c.cm. 

Five  c.mm.  of  this  mixture  are  placed  on  a  slide  and  allowed  to  dry. 
The  actual  number  of  leucocytes  is  counted  by  using  a  mechanical 
stage  and  an  oblong  diaphragm  in  the  eye-piece. 

The  reel  cells  may  also  be  counted  by  adding  5  c.mm.  of  the  first  (methyl 
violet)  dilution  to  995  c.mm.  of  8  per  cent,  solution  of  eosine.  Five  c.mm. 
of  this  are  allowed  to  dry  on  a  slide  and  the  total  number  of  red  corpuscles 
is  counted. 

1  Brit.  Med.  Joum.,  1905. 

2  Brit.  Med.  Joum.,  1903. 


ENUMEKATION   OF   LEUCOCYTES   AND   BLOOD-PLATES     17 

Enumeration  of  the  Blood-Plates. — Some  recent  work  has  indi- 
cated that  there  are  changes  in  the  number  of  blood-plates  corresponding 
to  phases  of  disease,  but  it  may  be  said  that  the  enumeration  of  blood- 
plates  does  not  yield  results  of  clinical  value  in  any  way  commensurate 
with  the  trouble  involved.  The  chief  difficulty  is  the  great  tendency 
of  the  plates  to  adhere  to  glass,  and  for  this  reason  the  use  of  pipettes 
has  been  criticised.  Tschistowitsch,1  however,  obtained  results  by  the  use 
of  the  pipette  and  counting  chamber  apparently  more  accurate  than  with- 
out them.  By  the  pipette  and  counting  chamber  method  the  procedure 
is  the  same  as  that  for  counting  leucocytes,  except  that  the  diluting  fluid 
is  different.     The  following  solutions  may  be  employed  : — 

(1)  Affanassiew's  solution — 


Sodium  chloride 

0*8  grm. 

Witte's  peptone  • 

0*6  grm. 

Distilled  water 

100  c.c. 

Methyl  violet 

.       1  in  100,000. 

(2)  Pratt's  solution — 

Sodium  metaphosphate  (Merck) 

2  grms. 

Sodium  chloride 

0.9  grm. 

Distilled  water  . 

100  c.c. 

Another  method  is  either  to  place  a  drop  of  preserving  fluid  on  the 
skin  before  making  a  puncture,  or  to  place  a  drop  of  preserving  fluid  on 
a  slide  and  touch  the  drop  of  blood  with  the  fluid.  The  red  cells  and 
plates  are  counted  in  a  succession  of  fields  and  the  proportion  of  plates 
to  red  cells  is  determined.  The  number  of  red  cells  per  cubic  milli- 
metre is  then  counted  in  the  ordinary  way,  and  thus  we  may  estimate 
the  number  of  plates.  Suitable  fluids  for  this  estimation,  in  addition 
to  the  above,  are  1  per  cent,  osmic  acid  and  equal  parts  of  glycerine 
saturated  with  dahlia,  and  sodium  chloride,  2  per  cent. 

"We  have  obtained  the  best  results  by  using  Pratt's  solution  and 
ascertaining  the  proportion  of  plates  to  red  corpuscles. 

1  Folia  Hcematologica,  iv.  1907. 


CHAPTER  III 

ESTIMATION"  OF  HAEMOGLOBIN:   THE  COLOUR  INDEX: 
CARE  OF  INSTRUMENTS 

Estimation  of  Haemoglobin. — The  amount  of  haemoglobin  present  in 
a  unit  of  fluid  is  stated  as  a  percentage  of  the  amount  in  the  same  unit 
of  healthy  adult  human  blood.  Numerous  instruments  for  estimating 
the  haemoglobin  percentage  are  available.  They  may  be  divided  into 
two  groups — 

(1)  Those  in  which  a  measured  sample  of  blood  is  diluted  until  it 
matches  a  fixed  standard. 

(2)  Those  in  which  a  measured  sample  of  blood  in  fixed  dilution 
is  compared  with  a  series  of  standards. 

1.  (a)  Goivers'  Hcemoglobinometer.  —  This  instrument  comprises  a 
pipette  to  measure  20  c.mm.  of  blood,  a  tube  containing  a  standard 
solution  of  picro-carmine  in  gelatine,  a  graduated  tube  for  diluting  the 
sample,  and  a  bottle  and  dropper  for  distilled  water. 

Procedure.  —  A  few  drops  of  distilled  water  are  placed  in  the 
graduated  tube.  Twenty  c.mm.  of  blood  are  sucked  up  into  the  pipette 
and  blown  into  the  water  in  the  graduated  tube.  The  blood  and  water 
are  gently  shaken  up  to  dissolve  out  the  haemoglobin.  More  water  is 
now  added  by  means  of  the  dropper  until  the  diluted  blood  matches 
the  colour  of  the  standard  tube.  It  is  not  advisable  to  attempt  accurate 
matching,  but  the  mean  point  between  under-dilution  and  over-dilution 
should  be  taken  as  the  reading.  The  comparison  should  be  made  in 
daylight,  unless  the  special  tubes  now  supplied  for  use  with  artificial 
light  are  available.  Both  tubes  should  be  held  level  with  the  eyes 
and  against  a  white  background.  The  position  of  the  tubes  should  be 
transposed  from  time  to  time.  The  figures  on  the  graduated  tube 
indicate  the  percentage  of  haemoglobin  present.  Healthy  blood  should, 
of  course,  retain  a  deeper  colour  than  the  standard  till  the  mark  100  is 
reached.  Blood  deficient  in  haemoglobin  matches  the  standard  before 
enough  water  to  bring  the  solution  up  to  the  mark  100  has  been  added. 

The  instrument  is  cheap,  simple,  and  sufficiently  accurate,  but  the 

18 


ESTIMATION   OF   HAEMOGLOBIN 


19 


standard  tube  is  apt  to  fade  in  colour  at  a  varying  rate.  At  one  time 
we  made  a  series  of  observations  with  the  same  blood  on  a  number  of 
instruments  which  had  been  in  use  for  some  years,  and  found  that  the 
readings  varied  as  much  as  40  per  cent. 

(b)  Halclanes  Hcemoglobinometer. — This  modification  of  Gowers'  in- 
strument has  the  following  advantages  : — 

(1)  The  standard  is  a  definite  one,  being  a  1  per  cent,  solution  of 


Fig.  13.— Haldane's  Hcemoglobinometer. 

A.  The  standard  tube  containing  a  solution  of  CO  hemoglobin.    B.  The  graduated  tube.    C.  The  stand. 
D.  The  pipette.    E.  Drop  bottle  for  distilled  water.    G.  The  connecting  tube  for  gas. 

blood  containing  the  average  amount  of  haemoglobin  in  health  saturated 
with  carbon  monoxide  (CO).  The  solution  should  have  an  oxygen 
capacity  of  18 '5  per  cent,  as  tested  by  the  ferricyanide  method.  The 
standard  may  thus  be  tested  at  any  time. 

(2)  The  standard  solution  is  permanent. 

(3)  The  instrument  may  be  used  either  by  daylight  or  artificial 
light. 

(4)  The  haemoglobin  to  be  determined  is  converted  into  CO 
haemoglobin  and  a  solution  of  this  is  tested  against  a  CO  haemoglobin 
standard. 

A  limitation  to  the  use  of  the  instrument  is  the  necessity  for  a 
convenient  supply  of  coal  gas. 

Procedure. — The  initial  steps  are  the  same  as  for  Gowers'  instru- 


20 


ESTIMATION   OF  HEMOGLOBIN 


ment.  Some  water  is  first  placed  in  the  graduated  tube,  the  blood  is 
added,  and  then  by  means  of  a  tube  supplied  with  the  apparatus  the 
air  in  the  graduated  tube  is  replaced  by  coal  gas  from  an  ordinary 
burner.  The  end  of  the  tube  is  closed  with  the  finger  and  the  tube  is 
then  inverted  several  times  until  the  haemoglobin  is  saturated  with  CO. 
More  water  is  now  added  with  the  same  precautions  as  for  G-owers' 
instrument,  and  the  mean  between  under-dilation  and  over-dilution 
taken  as  the  reading. 

(c)  Sahli's  Hcemoglobinometer. — The  principle  of  this  instrument  is 
the  same  as  that  of  Gowers'. 


Fig.  14. — Von  FleischiAs  HiEMOGLOBiNOMETER. 

0.  The  container,  a.  The  compartment  for  diluted  blood,  a'.  The  compartment  for  distilled  water. 
A'.  The  glass  wedge.  P.  The  graduated  scale.  T.  E.  The  rotating  screw.  M.  The  indicator.  S.  The 
reflecting  surface. 


The  standard  colour-tube  contains  a  1  per  cent,  solution  of  acid 
haematin.  The  graduated  tube  is  filled  up  to  the  mark  at  10  per  cent, 
with  decinormal  hydrochloric  acid.  The  blood  to  be  examined  is  added 
to  this  acid,  and  in  a  few  minutes  its  haemoglobin  is  broken  up  and  the 
pigment  becomes  acid  haematin.  We  have  now  simply  to  dilute  this 
specimen  of  acid  haematin  until  it  matches  the  acid  haematin  standard. 
The  level  of  the  fluid  in  the  graduated  tube  indicates  the  percentage 
of  haemoglobin.     The  colour-tube  is  apt  to  deteriorate  with  age. 

2.  (a)  Von  FleischVs  Hcemoglobinometer. — This  instrument  consists 
of  a  cylindrical  chamber  divided  into  two  compartments  which  is  set 
over  an  aperture  in  a  stage  resembling  that  of  a  microscope. 


ESTIMATION   OF   HAEMOGLOBIN  21 

Below  the  stage  a  wedge-shaped  piece  of  coloured  glass  lies  under 
one  compartment  and  can  be  moved  by  a  milled  screw,  so  that  any 
thickness  can  be  brought  under  the  compartment,  the  position  of  the 
wedge  being  indicated  by  a  scale. 

Light  from  a  lamp  is  reflected  from  a  white  cardboard  disc  up 
through  the  wedge  and  the  two  compartments.  A  self-filling  pipette 
mounted  on  a  handle  serves  to  collect  and  measure  the  sample  of  blood. 

Procedure. — Half  fill  one  compartment  with  distilled  water.  Dip 
the  point  of  the  pipette  sideways  into  a  drop  of  blood.  Wipe  its 
exterior.  Plunge  the  pipette  into  the  water  in  the  compartment  and 
wash  out  the  blood.  Now  completely  fill  this  compartment  by  adding 
water,  and  fill  the  other  to  be  placed  over  the  glass  wedge  with  dis- 
tilled water.  Daylight  being  excluded,  the  observer  takes  such  a 
position  that  the  two  compartments  are  divided  vertically  (right  and 
left)  and  not  horizontally.  By  means  of  the  milled  screw  the  position 
of  the  wedge  of  glass  is  altered  until  the  colour  in  the  two  compartments 
is  similar.  In  making  the  observation  a  series  of  glances  should  be 
employed  and  continuous  staring  avoided. 

It  is  an  advantage  to  look  through  a  tube  made  of  a  roll  of  black 
paper.  Use  little  light,  and  move  the  wedge  with  short,  quick  turns 
and  not  gradually.  The  reading  is  shown  by  the  number  on  the  scale 
opposite  the  indicator. 

A  diaphragm  with  an  oblong  slit  crossing  the  two  compartments 
may  be  employed  to  minimise  the  difficulty  arising  from  the  fact  that 
the  thickness  of  the  wedge  of  glass  and  consequently  the  depth  of 
colour  varies  in  each  field. 

(b)  Fleischl-Miescher  Hcemoglobinometer. — This  modification  is  essenti- 
ally the  same  as  the  original  Fleischl  instrument.  A  pipette  similar  to 
that  of  Thoma  is  supplied  for  diluting  the  blood.  It  is  graduated  to  give 
dilutions  of  one  in  either  one,  two,  or  three  hundred.  Two  cells,  one 
15  and  the  other  12  mm.  deep,  are  supplied  in  order  that  the  observa- 
tions may  be  controlled.  The  partition  dividing  the  chamber  projects 
to  fit  a  groove  in  a  cover-glass.  A  slotted  diaphragm  shuts  off  all  but 
the  central  portion  of  the  fields  for  comparison. 

(c)  Oliver's  Hcemometer. — The  principle  of  von  Fleischl's  apparatus 
is  employed,  but  the  standard  is  altered  in  a  series  of  definite  gradations. 
Oliver's  instrument  consists  of  a  camera  tube,  a  blood-cell  and  cover- 
glass,  a  series  of  circular  standards  in  wooden  blocks,  and  riders,  a 
self-filling  pipette,  and  a  rubber-capped  pipette  with  rubber  tubing  on 
its  end  for  emptying  the  self-filling  pipette. 


22 


ESTIMATION  OF  HAEMOGLOBIN 


Procedure. — Fill   the  measuring   pipette  with   blood,  wipe  it,  and 
immediately  fit  the  rubber  end  of  the  capped  pipette  containing  water 


Fig.  15. — Oliver's  H^emometer. 

I.  The  series  of  standard  colour  discs.    6.  Pricker,    c.  Self-filling  measuring  pipette,    d.  The  diluting 
pipette,    e.  The  blood  chamber. 


on  to  its  pointed  end,  and  wash  out  the  blood  into  the  cell.  Add  water, 
and  stir  with  the  handle  of  the  measuring  pipette  till  the  blood-cell 
is  full.     Slide  on  the  cover-glass.     Note  which  standard  approximately 


ESTIMATION    OF   HAEMOGLOBIN  23 

matches  the  colour,  and  then  compare  more  accurately  by  looking 
through  the  camera  tube.  It  may  be  necessary  to  use  a  rider  in  order 
to  secure  accurate  matching.  The  reading  is  indicated  by  numbers 
opposite  each  standard. 

Two  sets  of   standards  are  sold.     One  is  for  use  by  daylight,  the 


■Fig.  16. — Camera  Tube  for  Use  with  Oliver's  Hjemometer. 

other  for  artificial  light.     For  the  latter  a  Christmas   tree  candle  is 
recommended. 

(d)  Dare's  Hcemoglohinometer. — Undiluted  blood  is  allowed  to  pass 
by  capillarity  into  a  slit  between  two  little  glass  plates.  The  charged 
plates  are  then  slipped  into  a  window  in  the  instrument  beside  a  colour- 
prism.  The  reading  is  made  through  a  telescope  which  magnifies  the 
blood  and  the  standard.  The  illumination  is  by  candle-light,  but  the 
examination  need  not  be  carried  out  in  a  dark  room.  The  standard 
colour-prism  is  rotated  till  the  colours  match  and  a  knife  edge  indicates 
the  result. 


24  ESTIMATION   OF  HEMOGLOBIN 

The  instrument  is  expensive  and  fragile,  and  the  examination  must 
be  made  rapidly  before  clotting  occurs,  as  this  interferes  greatly  with 
the  accuracy  of  the  reading. 

(e)  Tallqvist's  H'.emoglobinometer. — This  has  the  advantage  of  great 
simplicity  and  is  sufficiently  accurate,  with  practice  in  using  it,  and 
control  at  first  by  other  methods,  for  most  clinical  work.  A  drop  of 
blood  is  allowed  to  fall  on  standard  blotting-paper  and  the  stain  is 
matched  against  a  series  of  colours  on  a  lithographic  scale,  indicating 
from  10  to  100  per  cent,  of  hsemoglobin.  The  tendency  of  beginners 
is  always  to  read  too  high,  partly  because  the  colouring  is  based  on 
von  Fleischl's  haemoglobinometer,  whose  normal  is  90  per  cent. 

(f)  Hall's  Rotatory  Hwmoglobinometer. — The  principle  is  the  same 
as  the  above.  The  coloured  standards  are  rotated  till  they  match  a 
blood  stain. 

The  Ferrometer. — The  amount  of  iron  in  blood  may  be  estimated 
directly.  The  most  simple  apparatus  for  clinical  use  is  the  modification 
of  Jolles'  instrument  made  by  Keichert.  It  is  used  in  conjunction  with 
the  von  Fleischl  haemoglobinorueter. 

Other  Methods. — The  hsemoglobinometers  of  Hayem  and  Malassez 
are  not  in  common  use.  For  a  discussion  of  heemoglobinometry  and 
description  of  the  chromophotometer  and  wedge-haemoglobinometer,  see 
Brugsch,  Folia  Hamiatologica,  ix.  1  Teil,  1910,  p.  201. 

The  Colour  Index. — The  colour  index  expresses  the  amount  of  the 
haemoglobin  complement  per  corpuscle.  It  is  obtained  by  dividing  the 
percentage  of  haemoglobin  by  the  percentage  number  of  corpuscles  as 
compared  with  blood  containing  5,000,000  per  c.mm.  Thus  the  colour 
index  in  a  person  with  100  per  cent,  hfemoglobin  and  5,000,000  red 
cells  per  c.mm.,  i.e.  100  per  cent.,  would  be  unity.  In  the  case  of  red 
cells,  2,500,000  and  haemoglobin  60  per  cent,  the  colour  index  would  be 
60 

ar1* 

The  colour  index  is  readily  obtained  by  dividing  the  first  three 
figures  (or  two  figures  when  the  number  is  under  one  million)  of  the 
blood  count  by  five  and  then  dividing  the  haemoglobin  percentage  by 
the  resulting  number,  or,  what  comes  to  the  same  thing,  multiplying 
the  first  two  figures  of  the  count  (or  one  figure  when  the  number  is 
under  one  million)  by  two  and  then  dividing  the  haemoglobin  percentage 
by  the  resulting  figure. 

The  colour  index  reaches  its  greatest  height  in  cases  of  pernicious 


ESTIMATION  OF  HEMOGLOBIN  25 

anaemia,  and  the  lowest  indices  are  found  in  chlorosis.  In  secondary 
anaemia  the  colour  index  is  generally  less  than  one,  but  is  seldom  or 
never  so  low  as  in  chlorosis.  In  very  severe  secondary  anaemia  the 
colour  index  is  higher  than  in  less  serious  cases. 

Care  of  Instruments. — Scrupulous  cleanliness  is  essential  for  the 
satisfactory  use  of  the  foregoing  instruments.  Especially  is  this  the 
case  regarding  pipettes,  and  never  under  any  circumstances  should  a 
pipette  be  put  away  dirty. 

The  short  thick-walled  pipettes  of  von  Fleischl  and  Oliver's 
apparatus  are  readily  cleaned  by  drawing  a  stout  thread  through 
them  by  means  of  a  loop  of  fine  wire,  which  should  be  entered  at  the 
pointed  end. 

Particular  attention  should  be  paid  to  pipettes  of  the  Thoma-Zeiss 
type.  Immediately  after  use  the  remaining  fluid  should  be  blown  out, 
preferably  in  the  case  of  the  "  red "  pipette  at  least,  through  the  wide 
end.  Water  should  then  be  drawn  through  the  pipette  and  blown  out, 
and  the  process  repeated  a  second  time. 

The  same  is  next  done  with  absolute  alcohol  and  then  with  ether. 
The  object  of  this  is,  firstly,  to  remove  all  albuminous  material,  and 
secondly,  to  leave  the  interior  of  the  pipette  thoroughly  dry,  so  that 
when  it  is  used  again  the  diluted  blood  will  advance  evenly  to  fill 
the  bulb.  In  cleaning  the  pipette  it  is  very  convenient  to  slip  a  tube 
attached  to  a  rubber  ball  over  its  point.  The  fluids  can  then  be  more 
forcibly  expelled,  and  all  risk  of  blowing  saliva  into  the  pipettes  is 
avoided. 

If  pipettes  are  not  promptly  cleaned  a  film  which  is  not  easily 
removed  tends  to  form  on  their  inner  surface.  This  is  more  likely  to 
occur  in  the  case  of  the  leucocyte  pipette,  and  it  is  worth  while  from 
time  to  time  to  fill  it  with  liquor  potassee  and  leave  it  for  an  hour  or 
two.  The  softened  and  loosened  film  is  then  blown  out  through  the 
wide  end  and  the  pipette  is  thereafter  cleaned  in  the  ordinary  way. 
Another  penalty  of  neglect  is  the  precipitation  of  salts  of  Hayem's 
solution  through  evaporation  at  the  point  of  the  pipette.  Prolonged 
soaking  in  water  may  be  necessary  to  remove  this  deposit.  If  pipettes 
cannot  be  cleaned  immediately  after  counting  is  finished,  they  should  be 
placed  in  clean  water  to  prevent  evaporation  and  deposit,  or  closed  at 
both  ends  with  a  rubber  band  as  already  described.  Pipettes  should, 
however,  never  be  cleaned  out  until  the  observer  is  satisfied  that  his 
counts  are  correct,  as  it  may  be  necessary  to  count  a  second  drop. 


26  ESTIMATION  OF  HAEMOGLOBIN 

A  little  clot  readily  forms  at  the  extremity  of  the  Thoma-Zeiss 
pipettes.  If  a  pin  or  needle  be  used  to  remove  this,  the  glass  will 
almost  certainly  be  chipped.  A  fine  wire  or  a  strong  horse  hair  may 
be  used  carefully,  but  it  is  not  an  unknown  accident  for  the  wire  to 
break,  and  then  the  last  state  of  that  pipette  is  worse  than  the  first. 

An  obstinate  clot  may  sometimes  be  got  rid  of  by  digesting  it  out 
with  pepsin  and  hydrochloric  acid. 

The  counting  slide  is  to  be  cleaned  with  cold  water,  and  occasion- 
ally washed  with  soap  and  cold  water.  Hot  water,  ether,  and  alcohol 
are  not  to  be  used,  as  they  loosen  the  cement  which  keeps  the  ruled 
table  and  glass  plates  in  place.  Water  is  usually  sufficient  for  the 
cover-glass,  but  it  is  none  the  worse  for  an  occasional  cleansing  with 
soap  and  water  followed  by  absolute  alcohol. 


CHAPTER  IV 

EXAMINATION   OF   STAINED   FILMS— PROCEDURE   AT 

THE  BEDSIDE 

Examination  of  Stained  Films. — The  importance  of  this  method  is  as 
much  under- estimated  as  the  difficulties  in  carrying  it  out  are  over-rated. 
A  well-prepared  blood-film  is  a  page  of  information  to  him  who  can 
read  it,  and  in  spite  of  assertions  to  the  contrary  we  maintain  that,  in 
the  great  majority  of  cases,  the  experienced  hsematologist  can  tell  from 
a  good  blood-film  the  number  of  red  cells  per  c.mm.  to  within  half 
a  million,  provided  he  knows  the  haemoglobin  percentage;  and  the 
number  of  leucocytes  (unless  they  are  markedly  excessive)  to  within  a 
thousand,  especially  if  he  has  made  the  film  himself.  The  films  may  be 
spread  on  either  slides  or  cover-slips,  and  may  either  be  treated  while 
wet  or  allowed  to  dry  before  staining.  We  would  urge  the  great 
importance  of  making  well-spread  films  to  work  on.  The  staining  of 
a  mess  of  blood-clot  or  a  clump  of  crushed  and  distorted  blood-cells 
gives  just  the  same  satisfaction  as  developing  a  photographic  plate 
which  has  been  two  or  three  times  exposed.  And  just  as  the  careful 
photographer  can  have  his  plates  finished  for  him  by  the  professional 
with  results  satisfactory  to  both,  so  he  who  doubts  his  hematological 
powers  can  easily  obtain  all  the  information  a  blood-picture  can  give 
by  posting  a  good  film  to  an  expert. 

Spreading  the  Film. — We  much  prefer  the  use  of  cover-slips.  Their 
greater  flexibility  permits  of  more  even  spreading.  They  are  more 
economical,  inasmuch  as  less  reagent  is  required,  and  where  several 
samples  are  required  they  are  less  bulky  and  more  easily  stored. 

Seven-eighth  inch  squares  or  circles  should  be  used.  Number  1 
thickness  is  preferable  for  high-power  work,  but  the  beginner  will 
perhaps  be  well  advised  to  use  number  2.  They  Must  he  Clean.  Many 
elaborate  formulee  for  cleaning  them  have  been  proposed,  but  are 
unnecessary.  If  only  a  few  covers  are  to  be  cleaned  at  one  time,  soap 
and  water,  followed  by  a  rinsing  in  clean  water,  and  drying  with  a  clean, 
old,  soft  handkerchief,  is  all  that  is  necessary.     If  a  larger  number  are 

27 


28  EXAMINATION   OF   STAINED   FILMS 

wanted  it  is  better  to  use  nitric  acid.  This  should  be  poured  into  a 
cylindrical  urine  glass  and  the  covers  allowed  to  drop  one  by  one  from 
the  hand  into  it.  They  may  be  left  for  half  a  minute,  then  the  nitric 
acid  is  poured  back  into  the  bottle,  the  urine  glass  filled  with  water,  and 
with  one  hand  over  the  mouth  inverted  and  reinverted  several  times. 
The  water  is  then  poured  away,  and  the  washing  repeated  several  times 
till  all  trace  of  the  acid  is  gone.  The  covers  are  allowed  to  drain  and 
then  put  into  absolute  alcohol,  in  which  they  may  be  left  till  required, 
or  dried  at  once.  It  is  not  wise  to  dry  too  many  at  a  time,  as  they 
become  dusty  very  quickly.  Glacial  acetic  acid,  fluid  soap,  or  lysol  may 
be  used  instead  of  the  nitric  acid.  The  covers  may  be  held  in  forceps 
or,  provided  only  the  edges  are  touched,  between  the  finger  and  thumb. 

A  freshly  exuded  drop  of  blood  is  lightly  touched  with  the  centre  of 
a  cover-glass.  The  skin  should  not  be  touched.  The  charged  cover- 
slip  should  then  be  allowed  to  drop  on  a  second  one  and  the  blood 
will  then  spread  out  into  a  film.  The  cover-slips  should  immediately 
be  slipped  apart  by  a  gliding  movement,  without  either  pressing  or 
lifting. 

Some  practice  is  requisite  in  order  to  choose  the  moment  when  the 
exuding  drop  of  blood  is  of  the  right  size.  If  too  large  a  quantity  be 
taken  up  the  cover-slips  never  come  into  close  enough  contact  to  spread 
a  film,  and  if  too  small  an  amount  be  taken  the  cells  may  be  distorted. 
A  drop  of  suitable  size  should  spread  out  to  cover  at  least  three-quarters 
of  each  cover-slip,  with  no  heaping  up  of  blood  at  one  side,  although  in 
certain  cases  a  small  quantity  of  thickly  smeared  blood  at  one  edge  may 
be  an  advantage. 

The  cover-glasses  are  more  easily  slipped  apart,  when  squares  are 
used,  if  they  are  applied  to  each  other  so  that  the  corners  do  not 
coincide,  thus  leaving  projecting  points  of  each  free  from  contact  with 
the  other. 

The  films  may  either  be  allowed  to  dry  or  be  treated  by  the  wet 
method.  For  the  former,  films  usually  dry  sufficiently  rapidly  without 
special  manipulation.  In  a  cold  damp  atmosphere  they  may  be  gently 
heated,  and  if  held  in  the  fingers  rather  than  forceps  the  danger  of 
overheating  is  very  slight. 

Films  made  on  Slides. — A  drop  of  blood  is  touched  by  a  slide  near 
its  end,  and  the  portion  adhering  to  it  may  be  either  pushed  along  it  by 
another  slide  with  a  rounded  edge,  so  held  that  the  drop  of  blood  lies  in 
an  angle  of  135°,  or  drawn  along  by  a  second  slide,  so  held  that  the  drop 
lies  in  an  angle  of  45°  between  the  two  slides. 


EXAMINATION   OF  STAINED   FILMS  29 

Another  method  which  has  always  seemed  to  us  to  have  little  to 
commend  it  is  to  touch  a  drop  of  blood  with  a  cigarette  paper  or  strip 
of  gutta-percha  tissue,  apply  this  to  a  slide,  and  as  soon  as  the  blood 
has  spread  out  to  draw  it  along  and  off  the  slide. 

The  main  disadvantage  of  these  slide  methods  is  that  the  larger 
leucocytes  are  carried  out  to  the  edges  and  end  of  the  film,  so  that 
it  is  impossible  to  make  an  accurate  differential  count.  They  should 
not  be  used,  therefore,  for  ordinary  purposes,  bat  are  of  use  when  a 
large  quantity  of  blood  is  to  be  examined,  as,  for  instance,  in  cases  of 
malaria  with  few  parasites,  and  in  other  parasitic  diseases ;  but  for 
these  the  method  of  thick  dehasmoglobinised  films  is  preferable  (see 
Chap.  XXXVII. ). 

Preparation  of  Dry  Films — Fixation. — Such  excellent  and  simple 
methods  of  combined  fixation  and  staining  are  now  available  that  a 
special  paragraph  on  fixation  is  almost  an  anachronism,  but  in  certain 
circumstances  separate  fixation  is  necessary.  Its  object  is  twofold — to 
conserve  the  haemoglobin  of  the  red  cells,  which  would  otherwise  be 
dissolved  out  by  watery  staining  solutions,  and  to  fix  the  leucocyte 
granules. 

Fixation  oy  Heat. — This,  the  original  method,  has  been  given  up  for 
general  purposes,  but  is  still  by  far  the  best  when  Ehrlich's  triple  stain 
is  to  be  used.  When  a  steriliser  is  available,  films  may  be  heated  to 
110°  C,  and  kept  at  that  temperature  for  from  ten  minutes  to  an  hour 
and  then  gradually  allowed  to  cool.  With  the  shorter  exposure  a  heat 
of  120°  C.  does  no  harm.  Cabot  recommends  rapid  heating  to  140°  or 
150°  C,  followed  by  rapid  cooling.  This  last  method  gives  occasionally 
very  beautiful  results,  but  is  rather  uncertain,  the  margin  between 
over-  and  under-heating  being  narrow.  Various  small  heaters  consisting 
of  a  metal  oven,  thermometer  and  lamp  are  on  the  market.  More 
simple  heat  fixation  may  be  effected  by  passing  the  film  from  twelve  to 
twenty  times  through  a  Bunsen  or  spirit  flame,  but  the  results  are  apt 
to  be  uncertain.     The  slow  method  is  really  the  best. 

Chemical  Fixation. — The  most  useful  methods  are  : — 

(a)  Formol- Alcohol. — Films  are  immersed  for  four  minutes  in  a  mixture  of 
formaline  10  parts  and  absolute  alcohol  90  parts,  and  are  then  washed  in 
water  and  stained. 

(b)  Alcohol  and  Ether. — Films  are  placed  in  a  mixture  of  equal  parts 
of  absolute  alcohol  and  ether  for  half  an  hour.  Longer  fixation  does  no 
harm. 

(c)  Formol  Vapour. — Films  are  exposed  to  the  vapour  under  a  bell-jar  for 
from  a  half  to  one  minute. 


30  EXAMINATION  OF  STAINED   FILMS 

Staining  of  Dey  Films 

Very  numerous  methods  are  in  vogue,  and  many  possess  special 
advantages.  Ehrlich's  triple  stain  has  a  time-honoured  reputation  for 
bringing  out  leucocyte  granules,  but  it  is  now  largely  superseded  by 
some  of  the  eosine-methylene  blue  methods.  The  use  of  certain  com- 
binations of  eosine  and  methylene  blue  results  in  the  production  of  a 
blue  colour  in  basophil  cytoplasm  and  a  violet  or  crimson  colour  in 
nuclei  and  some  other  structures — Romanowshy  effect}  The  red  colour 
is  not  due  to  the  direct  effect  of  the  eosine,  though  this  dye  at  the 
same  time  colours  oxyphil  structures.  The  method  brings  out  very 
full  detail,  and  is  exceedingly  useful  in  the  study  of  blood-parasites. 
The  effect  is  obtained  by  the  use  of  Giemsa's,  Leishman's,  and  Pappen- 
heim's  methods  described  below. 

The  following  account  is  by  no  means  exhaustive : — The  necessary 
manipulations  are  greatly  facilitated  by  the  use  of  Cornet's  forceps  to 
hold  the  cover- slips.  A  fairly  efficient  substitute  is  a  wooden  match 
with  a  split  end  and  a  notch  to  mark  the  loaded  side  of  the  cover -glass. 

Eosine  and  Methylene  Blue. — Fix  in  formol-alcohol  for  four  minutes. 
"Wash  in  water.  Stain  with  saturated  watery  eosine  for  four  minutes. 
Wash  in  water.  Stain  with  saturated  watery  methylene  blue  for  from 
thirty  seconds  to  two  minutes.  Wash  in  water,  dry,  and  mount  in 
Canada  balsam. 

Piecl  cells  are  stained  pink ;  nuclei,  blue  ;  neutrophil  granules,  pink ; 
eosinophil  granules,  scarlet ;  mast-cell  granules,  violet  or  crimson. 

Giemsa's  Stain — 

Eosine,  extra-hochst  0*5  per  1000  in  distilled  water  10  c.c. 

Azur  II.,  Griibler  0"8  per  1000  in  distilled  water     .  1  c.c. 

Fix  films  in  absolute  alcohol  and  stain  for  from  fifteen  to  thirty 
minutes.  Nuclear  structure  is  well  demonstrated.  Mast-cell  granules 
are  stained  a  bright  crimson. 

JEhrlich's  Triple  Stain — 

Saturated  watery  solution  of  orange  G. 
Saturated  watery  solution  of  acid  fuchsin 
Saturated  watery  solution  of  methyl  green 
Distilled  water 
Absolute  alcohol 

1  For  a  useful  discussion  of  Romanowsky  staining  see  Scott,  Folia  Hmnatologica,. 
xii.  Archiv,  1911,  pp.  302,  363.  For  an  account  of  staining  methods  in  general  see 
Pappenheim,  Folia  Hwmatologica,  ix.  Archiv,  1910,  p.  572. 


14 

c.c. 

7 

c.c. 

12 

5  c.c. 

15 

c.c. 

15 

c.c. 

EXAMINATION   OF  STAINED   FILMS  31 

Shake  for  some  time,  then  add — 

Absolute  alcohol  .  .  .  .10  c.c. 

Glycerine  .  .  .  .  .10  c.c. 

These  solutions  are  to  be  measured  in  the  same  vessel,  without 
washing,  mixed  in  the  exact  order  given,  but  without  shaking  or 
stirring  until  after  the  first  amount  of  alcohol  has  been  added.  At  the 
end  of  the  procedure  the  whole  fluid  should  be  thoroughly  shaken  up. 

It  is  very  much  more  satisfactory  to  buy  this  stain  ready  made,  as 
a  very  slight  deviation  from  the  exact  order  given  alters  its  properties. 
In  making  up  the  stain  it  is  very  important  to  be  sure  that  the  solu- 
tions of  the  stains  used  are  really  thoroughly  saturated.  The^Rst 
results  are  obtained  after  fixation  by  heat.  The  films  should  be  then 
stained  for  five  minutes,  washed  rapidly  in  water,  dried,  preferably 
between  layers  of  filter  paper,  and  mounted  in  balsam.  The  red 
corpuscles  should  be  stained  orange,  nuclei  green,  neutrophil  granules 
a  crimson-purple,  eosinophil  granules  copper  colour.  Basophil  granules 
are  not  stained,  but  appear  in  the  cells  as  unstained  vacuoles.  The 
reason  for  this  is  that  the  basic  stain  used,  methyl  green,  is  a  fairly 
exact  chromatin  stain,  but  not  so  basic  as  methylene  blue,  so  that  it 
has  not  the  affinities  of  the  latter  stain  for  basophil  protoplasm  and 
basophil  granules.  Thus,  lymphocyte  protoplasm  is  stained  pink.  If 
the  preparation  has  been  overheated,  no  length  of  time  of  staining 
gives  a  satisfactory  picture.  The  preparation  looks  as  though  it  had 
been  washed  out  too  long,  while  with  underheating  the  red  corpuscles 
are  pink  or  crimson  instead  of  yellow,  and  nuclei  are  sometimes  well 
stained,  while  the  granules  lack  the  sharp  definition  of  a  properly  fixed 
specimen.  It  must  be  borne  in  mind  that  the  nuclear  staining  by 
methyl  green  is  not  so  deep  as  one  is  accustomed  to  in  methylene  blue 
preparations,  except  in  the  case  of  nucleated  reds  of  normoblastic  type, 
and  in  some  polymorphs.  Almost  all  other  nuclei  are  of  a  faint 
greenish-blue.  Fair  results  can  also  be  got  after  fixing  with  formaline 
alcohol  and  formaline  vapour,  and  even  with  alcohol  and  ether,  but 
they  are  seldom  so  sharp  as  after  heat.  There  is  nothing  in  blood 
pictures  which  equals  in  beauty  a  good  triacid  specimen,  but  the  stain 
is  no  longer  used  for  general  purposes.  It  is  reserved  for  cases  in 
which  it  is  desired  to  bring  out  neutrophil  granules,  especially,  for 
example,  when  one  wishes  to  make  a  differential  count  of  myelocytes 
and  lymphocytes  in  myelocythjemia.  It  is  a  very  satisfactory  marrow 
stain,  because  of  the  large  number  of  granular  cells  found  there. 


32  EXAMINATION   OF  STAINED   FILMS 

The  name  "  triacid "  which  is  sometimes  applied  to  it  is  really  a 
misnomer.  There  are  two  acid  stains  in  it  and  one  basic  one,  and 
presumably  two  neutral  combinations  also,  although  apparently  the 
more  powerful  is  that  formed  by  the  acid  fuchsin  and  methyl  green. 
The  term  "neutrophil"  was  originally  applied  by  Ehrlich  to  the 
granules  of  the  ordinary  polymorphs  because  of  their  affinity  for  this 
neutral  stain.  The  term  triacid  was  given  at  first  to  a  mixture  of  the 
three  acid  stains — indulin,  nigrosin,  and  aurantia — which  was  devised 
by  Ehrlich  for  eosinophil  (acidophil)  granules. 

Hccmatein  and  Eosine. — Fix  with  a  chemical  fixative.  Wash  in 
water.  Stain  with  hsematein  for  five  minutes  or  longer.  Wash  in 
water.  Stain  with  saturated  watery  eosine  for  two  minutes  or  longer. 
Wash  in  water,  dry  and  mount.  This  procedure  has  the  advantage  of 
elasticity  and  can  hardly  be  mismanaged.  Nuclear  structure  is  par- 
ticularly well  shown.  Its  disadvantages  are  that,  neutrophil  granules 
are  not  stained,  and  it  may  be  difficult  to  distinguish  nucleated  red 
cells  from  lymphocytes. 

Heidenhain's  Iron-Hcematoxylin  Method. — 1.  Fix  films  in  formol- 
alcohol  or  in  saturated  solution  of  corrosive  sublimate  in  0*75  per  cent, 
salt  solution,  then  wash. 

2.  Place  in  a  mordant  of  2'5  grms.  of  ferric  alum  dissolved  in  100 
c.c.  distilled  water  for  three  hours  or  longer. 

3.  Einse  in  distilled  water. 

4.  Stain  for  twelve  hours  or  longer  in  equal  parts  of  Weigert's 
hematoxylin  and  distilled  water. 

5.  Einse  in  tap  water. 

6.  Eeplace  in  the  iron  solution  to  bleach  and  differentiate,  checking 
the  process  by  frequent  examination  under  a  low  power. 

7.  Wash  for  ten  minutes  in  tap  water. 

8.  If  desired,  counter-stain  with  dilute  watery  eosine  and  wash. 

9.  Dry  and  mount. 

This  method  requires  too  much  time  for  ordinary  use,  but  is  of 
great  service  in  demonstrating  mitotic  figures,  granules,  and  centro- 
somes. 

Combined  Fixing  and  Staining  Methods 

Jenner's  Method. — This  stain  is  by  far  the  most  useful  of  all  the 
methods.  It  is  strictly  a  solution  in  methyl-alcohol  of  the  eosinate 
of  methylene  blue,  in  an  excess  of  methylene  blue.  The  solvent  used, 
which  must  be  Merck's  methyl-alcohol,  pure  for  analysis  and  free  from 


EXAMINATION   OF  STAINED   FILMS  33 

acetone,  has  a  special  fixing  action  on  red  corpuscles,  so  great  that 
the  immersion  of  the  film  for  half  a  minute  or  less  suffices  to  fix  them 
completely.  The  original  method  of  making  the  stain,  as  published  by 
Jenner,  was  unnecessarily  tedious.  Several  firms  of  manufacturing 
chemists  now  make  the  stain  in  tablet  form,  the  prescription  being  that 
one  tablet  shall  be  dissolved  in  10  c.c.  of  methyl-alcohol.  "We  have 
generally  found  that  a  better  stain  is  made  if  two  tablets  are  used  to 
the  same  amount.  Care  must  be  taken  that  the  bottle  in  which  the 
stain  is  put  be  absolutely  clean  and  dry.  If  larger  quantities  are 
required,  however,  it  is  easy  to  make  the  stain  by  the  following 
prescription : — 

Of  05  grm.  methylene  blue  (medic,  rein)  dissolved  in 
50  c.c.  methyl-alcohol,  take  25  c.c. 

Of  0*5  grm.  water  soluble  eosine  (yellowish)  dissolved  in 
50  c.c.  methyl-alcohol,  take  20  c.c,  mix,  and  add 
20  c.c.  of  methyl-alcohol.  This  improves  the  keep- 
ing qualities  of  the  solution,  and  does  not  weaken 
the  stain. 

The   fluid  is  immediately  ready  for   use,  although  it  improves  by 
being  kept  for  twenty-four  hours,  and  remains  good  for  months  if  the 
bottle  be  kept  tightly  corked.     If   the  methyl-alcohol  be  allowed  to 
evaporate  a  precipitate  is  formed  in   the  stain  which  spoils  the  pre- 
parations.    The  method  of  staining  is  to  drop  on  the  film,  held  in  a 
pair  of  Cornet's  forceps,  five  or  six  drops  of  fluid,  enough  to  cover  it 
thoroughly.     After  from  thirty  to  sixty  seconds  the  film  is  rapidly  washed 
in  distilled  water  until  the  edge  becomes  pink,  and  then  allowed  to 
dry  in  the  air,  being  tilted  on  its  side  so  that  the  lower  edge  of  the 
cover  drains  into  blotting-paper.     Artificial  heat  must  never  be  used 
to  dry  the  film,  as  a  certain  amount  of  differentiation  of  the  stain  goes 
on  in  the  slow  drying,  and  it  will  be  found  that  heated  films  are  always 
too  blue.     The  water  used  for  washing  out  must  be  distilled ;  ordinary 
tap  water  removes  the  blue  from  the  nuclei.     One  great  advantage 
with  this  stain  is  that  the  result  closely  approximates  to  that  obtained 
by  successive   staining  with  eosine  and  methylene  blue,  a  method  on 
which  much  of  our  nomenclature  is  based.     It  is  also  possible  to  bring 
out  by  it  the  special  staining  reactions  of  different  cells  and  corpuscles. 
Thus  a  film  stained  in  the  way  we  have  just  described  will  show  the 
reds  of   a  greyish  terra-cotta  colour,  the   nuclei  blue,  the  granules  of 
neutrophil  cells  purple,  those  of  eosinophils  pink,  and  of   basophils  a 
deep  blue  purple,  while  blood-plates  are  pale  blue,  and  all  such  details 

3 


34  EXAMINATION   OF   STAINED   FILMS 

as  polychromasia  and  basophilia  are  properly  brought  out.  On  the 
other  hand,  if  staining  be  prolonged  for  two  or  three  minutes,  or  the 
time  of  washing  be  increased,  the  red  part  of  the  stain  gains  the  upper 
hand,  and  therefore  eosinophil  granules  can  be  brought  out  specially 
well  in  this  way.  But  although  nuclei  continue  to  stain  well,  the 
finer  gradations  of  polychromasia  and  basophil  granules  in  the  reds 
are  apt  to  be  lost.  The  commonest  error  in  using  this  stain  is  to  stain 
too  long  and  wash  out  too  much. 

This  stain  is  also  very  useful  for  marrow  films,  but  should  then  be 
used  in  a  rather  different  way.  After  staining  for  a  minute  with  the 
original  fluid,  a  few  drops  of  distilled  water  should  be  dropped  from  a 
pipette  on  to  the  top  of  the  fluid,  with  which  it  rapidly  mixes.  This 
mixture  should  be  allowed  to  act  for  three  minutes,  and  the  film  then 
placed  in  distilled  water  for  three  minutes  more.  This  gives  a  better 
result  in  marrow  films  than  any  other  method. 

It  is  well  known  that  films  which  have  been  kept  longer  than  a 
month  or  two  will  not  stain  well  with  any  of  the  methyl-alcohol  fluids, 
but  Jenner  can  be  used  to  overcome  this  difficulty  also.  Fixing,  in 
films  which  have  been  kept  for  a  long  time,  is  quite  unnecessary,  and 
indeed  if  Jenner  be  used  alone  with  old  films  the  result  is  that  the  dry 
plasma  usually  stains  most  energetically,  the  red  corpuscles  remain 
unstained,  and  very  often  the  whites  as  well.  If,  however,  a  very 
dilute  solution  of  Jenner  in  distilled  water  be  made,  say  20  or  30  drops 
to  1  oz.  of  distilled  water,  and  the  films  allowed  to  remain  in  this  for 
any  time  up  to  twenty-four  hours,  a  very  satisfactory  differential 
staining  can  usually  be  obtained. 

Leishmans  Method. — The  stain  is  a  compound  of  alkaline  medicinal 
methylene  blue  and  eosine  (extra  B.  A.,  Griibler).  It  is  dissolved  in 
pure  methyl-alcohol  in  0*15  per  cent,  solution. 

1.  Apply  just  enough  stain  to  cover  the  film  and  leave  it  for  two 
minutes. 

2.  Add  drop  by  drop  distilled  or  tap  water  till  the  solution  and 
the  film  appear  pink,  then  allow  the  diluted  stain  to  act  for  three 
minutes. 

3.  Wash  in  distilled  or  tap  water,  dry  (avoiding  much  heat),  and 
mount  in  xylol  balsam. 

Bed  cells  are  pale  pink,  nuclei  purple,  neutrophil  granules  violet, 
eosinophil  granules  red,  basophil  granules  dark  blue  or  crimson,  organ- 
isms and  parasite  bodies  blue,  parasite  chromatin  brilliant  red. 


EXAMINATION   OF   STAINED   FILMS 


Panchromic  Methods 

Pappenheim  recommends  a  combination  of  Jenner's  and  Giemsa's 
method  as  bringing  out  the  best  possible  results.  The  Jenner  solution 
brings  out  the  neutrophil  and  eosinophil  granules,  while  the  Giemsa 
stain  intensifies  mast-cell  granules  and  defines  nuclear  structure. 

The  procedure  is  as  follows  : — 

Dry  films  are  fixed  and  stained  in  Jenner's  solution  for  three  minutes. 
Distilled  water  is  then  dropped  on  to  the  film  till  the  stain  acquires 
a  pinkish  colour.  The  dilute  stain  is  allowed  to  act  for  three  or  four 
minutes;  it  is  then  washed  off  in  distilled  water  and  immediately 
followed  by  Giemsa's  solution  (3  drops  in  2*3  c.cm.  of  distilled  water). 
After  five  minutes  the  film  is  washed  in  distilled  water,  dried  (not  over 
a  flame),  and  mounted. 

Pappenheim's  Panchromic  Mixture. — More  recently  Pappenheim1 
has  introduced  a  method  which  is  intended  to  bring  out  in  one 
preparation  all  the  different  affinities  for  basic  and  metachromatic 
dyes.  Dry  films  are  fixed  for  five  minutes  either  in  Jenner's  stain 
or  in  ecpial  parts  of  absolute  methyl  and  ethyl  alcohol.  They  are 
then  stained  for  from  five  to  ten  minutes  in  15  drops  of  the  stain 
diluted  in  10  c.cm.  of  distilled  water.  After  drying  in  air  the  films  are 
differentiated  in  a  mixture  of  methyl-alcohol  3  parts  and  acetone  1  part. 


tormula  tor  the  ste 

tin  is : — 

Methylene  blue   . 

1 

Toluidin  blue 

0-5 

Azur  I.     . 

1 

Methylene  violet 

0-5 

Eosine 

0-75 

Methyl-alcohol     . 

250 

Glycerine 

200 

Acetone  . 

Wet  Methods 

50 

1.  Films  are  rapidly  immersed,  as  soon  as  they  have  spread,  into 
a  fixing  solution,  and  throughout  the  staining  process  must  not  be 
allowed  to  dry.  Wet  films  may  be  fixed  in  formol-alcohol  or  corrosive 
sublimate  solution  and  stained  by  any  of  the  methods  mentioned  on 
pp.  30-32.  After  washing  they  are  dehydrated  in  absolute  alcohol, 
cleared  in  xylol,  and  mounted  in  balsam. 

1  Folia  Hcematologica,  xi.  1  Teil,  1911,  194. 


36  EXAMINATION   OF   STAINED   FILMS 

2.  A  simpler  method1  is  as  follows: — Films  are  plunged  into  a 
wide-mouthed  bottle  containing — 

Saturated  solution  of  eosine  in  absolute  alcohol         25  c.c. 
Pure  ether         .  .  .  .  .         25  c.c. 

Solution   of    corrosive    sublimate   in   absolute 

alcohol  (2  grms.  in  10  c.c.)     .  .  .5  drops. 

They  are  fixed  in  three  minutes,  but  may  be  left  for  twenty-four  hours. 
After  thorough  washing  they  are  stained  for  a  minute  in  saturated 
watery  solution  of  methylene  blue,  washed  in  water,  dehydrated  with 
absolute  alcohol,  cleared  in  xylol,  and  mounted  in  xylol  balsam. 

Choice  of  Staining  Methods. — For  general  use  we  unhesitatingly 
recommend  Jenner's  stain  as  the  most  suitable  and  convenient. 
Practically  its  only  limitations  are  that  it  does  not  keep  indefinitely 
and  that  it  does  not  succeed  without  some  trouble  in  staining  old 
films.  It  is  the  ideal  stain  for  one  who  is  examining  blood  twice  a 
week  or  more  frequently. 

Old  films  stained  with  Jenner  have  a  clirty-green  colour,  which  can 
sometimes  be  cleared  up  by  soaking  them  for  a  night  in  distilled  water. 

For  one  who  is  not  likely  to  examine  films  more  often  than  once 
a  month  we  recommend  fixation  in  formol-alcohol,  followed  by  eosine 
and  methylene  blue.  We  have  stained  films  ten  years  old  by  this 
method  with  fair  results. 

For  the  demonstration  of  parasites  Leishrnan's  stain  gives  excellent 
results  and  is  easily  applied,  but  it  is  not  so  satisfactory  for  general 
purposes  as  Jenner.  Neutrophil  and  eosinophil  granules,  polychromasia 
and  basophilia,  are  not  so  well  brought  out. 

For  micro-photography  iron-harniatoxylin,  haematein  and  eosine,  and 
Leishrnan's  method  are  much  superior  to  all  the  others. 

Wet  methods  are  only  required  for  fine  cytological  work.  Leuco- 
cytes are  fixed  as  spherules  and  are  not  flattened  out.  Bed  corpuscles 
are  always  distorted,  not  so  much  because  of  the  action  of  the  fixing 
agent,  as  because  they  have  been  distorted  in  making  the  films,  and 
have  not  time  to  return  to  their  normal  shape  before  fixation  takes 
place. 

In  all  cases  some  extra  films  should  be  made  and  held  in  reserve 
till  a  stained  specimen  has  been  examined.     By  so  doing  many  vain 
regrets  might  be  spared  for  patients  who  have  left  for  another  country 
or  even  another  world  before  a  new  supply  of  films  could  be  obtained. 
1  Gulland,  Brit.  Med.  Journ.,  13tli  March  1897. 


EXAMINATION   OF   STAINED   FILMS  37 

Procedure  at  the  Bedside. — A  great  deal  of  unnecessary  incon- 
venience is  sometimes  inflicted  on  patients  in  obtaining  the  blood 
for  examination.  A  complete  routine  examination  will  include  the 
examination  of  fresh  and  stained  films,  the  enumeration  of  red  and 
white  cells,  and  the  estimation  of  haemoglobin.  A  certain  amount  of 
method  will  be  a  distinct  advantage  to  observer  and  observed.  The 
following  articles  are  taken  to  the  bedside  and  should  be  conveniently 
arranged  upon  a  tray  —  a  small  table  should  be  prepared  for  its 
reception: — (1)  A  pricker;  (2)  a  well- washed  linen  cloth ;  (3)  solution 
for  conserving  red  corpuscles ;  (4)  solution  for  white  cells ;  (5)  the 
hsemoglobinometer  pipette;  (6)  the  blood  tube  or  chamber  of  the 
hremoglobinometer  containing  a  little  distilled  water ;  (7)  the  red 
corpuscle  pipette ;  (8)  the  white  cell  pipette ;  (9)  a  microscopic  slide ; 
(10)  an  envelope  bearing  the  patient's  name  and  the  date,  and  con- 
taining at  least  five  clean  cover-glasses. 

A  pair  of  forceps  for  manipulating  cover-slips  may  be  added  if 
desired.  The  instruments  are  arranged  to  hand,  the  stoppers  are 
removed  from  the  bottles,  and  the  slide  and  cover-slips  are  arranged 
on  the  envelope.  The  patient  is  asked  to  turn  the  head  away  from 
the  observer.  The  lobule  of  the  ear  is  rubbed  with  the  cloth,  which  is 
then  laid  behind  the  ear.  The  puncture  is  made,  and  as  a  rule  one 
puncture  should  be  sufficient  for  the  complete  examination.  The  first 
drop  of  blood  is  wiped  away.  The  hgemoglobinometer  pipette  is  now 
filled,  and  the  blood  is  blown  out  into  the  distilled  water  and  gently 
shaken.  The  white  cell  and  red  cell  pipettes  are  charged  in  succession 
and  laid  flat.  A  drop  of  blood  is  now  taken  up  on  a  cover-slip,  which 
is  dropped  on  the  slide.  Films  are  made  on  the  remaining  cover-slips, 
and  the  procedure  is  complete.  A  fresh  drop  of  blood  should  be  used 
for  each  pipette  and  each  pair  of  films.  Light  pressure  is  applied  to 
the  puncture  for  a  few  seconds.  The  films  as  soon  as  they  are  dry 
are  placed  in  the  envelope  and  the  tray  is  removed. 


CHAPTER  V 
SPECIAL  METHODS   OF  EXAMINATION 

A  vaeiety  of  special  methods  may  be  required  in  certain  cases. 

The  Viscosity  of  the  Blood. — The  viscosity  of  the  blood  depends 
mainly  upon  the  number  of  corpuscles  it  contains.  It  is  increased  to 
an  important  extent  when  the  number  of  red  corpuscles  is  excessive. 
Many  methods  of  estimating  the  viscosity  have  been  suggested.1  A 
simple  apparatus  is  that  of  Denning  and  Watson. 

The  essential  part  of  the  instrument  is 
a  U-shaped  capillary  tube,  with  one  arm  about 
6  cm.  long  and  the  other  much  shorter.  The 
end  of  the  long  arm  is  expanded  so  as  to  be 
readily  applied  to  the  lobule  of  the  ear;  the 
short  has  a  dilated  bulb  with  a  mark  m'  and 
m"  on  either  side  of  it.  The  instrument  is 
applied  to  the  ear  vertically  downwards,  and 
the  time  taken  for  blood  to  flow  from  m'  to 
m"  is  noted,  and  compared  with  the  time  taken 
by  distilled  water.  The  apparatus  supplied 
consists  of  six  such  tubes  which  differ  in  calibre, 
a  stop-watch,  and  a  pump  and  rubber  tube  for 
cleaning  the  pipettes  or  starting  the  flow  of 
blood.  If  the  blood  to  be  examined  is  very 
fluid  a  pipette  with  a  small  bore  should  be 
selected ;  if  the  blood  is  unduly  viscous  a  wide- 
bored  tube  should  be  chosen.  The  tube  must 
be  clean  and  must  be  at  the  same  temperature 
as  the  patient  when  applied.  The  column  of 
blood  should  be  unbroken.  If  need  be,  the  flow  of  blood  may  be  started 
by  applying  suction  to  a  rubber  tube  attached  to  the  short  arm.  The 
time  taken  by  the  passage  of  distilled  water  and  the  time  taken  by  the 

1  See  Folia  Hcematologica,  iv.  1907,  677  et  seq. 


m 


mJ 


Fig.  17. — Viscosimeter  op 
Denning  and  Watson. 


SPECIAL  METHODS  OF  EXAMINATION  39 

blood  sample  is  ascertained  with  the  aid  of  the  stop-watch.  The  result 
(obtained  by  dividing  the  water  time  by  the  blood  time)  is  expressed  as 
the  ratio  of  the  viscosity  of  blood  to  that  of  water. 

Estimation  of  Coagulation  Time. — In  normal  conditions  the 
coagulation  time  is  about  three  and  a  half  minutes.  Variations  have 
been  said  to  occur  with  the  time  of  day,  the  amount  of  exercise,  and  the 
kind  of  food,  but  in  an  important  paper  Addis  points  out  that  these 
variations  are  much  more  likely  to  be  due  to  variations  in  the 
temperature  at  which  the  observations  are  made.  Contact  between 
the  blood  and  the  tissues  is  an  important  factor.  Lee  and  White1 
found  that  coagulation  of  blood  drawn  directly  from  a  vein  took  place 
in  an  average  time  of  six  and  a  half  minutes,  while  blood  taken  from  a 
puncture  in  the  ear  clotted  in  three  minutes.  The  coagulation  time 
varies  considerably  in  disease,  but  in  only  a  few  conditions  is  a  know- 
ledge of  it  of  practical  value.  According  to  Addis  the  coagulation  time 
is  affected  in  bacterial  diseases  only  when  the  organisms  are  present  in 
the  blood.  Pneumococci  and  typhoid  bacilli  hasten  coagulation,  while 
staphylococci  and  streptococci  delay  it.  In  pneumonia  there  is  no 
doubt  that  a  rapid  coagulation  time  is  of  ill  omen. 

Coagulation  is  manifestly  delayed  in  haemophilia,  but  shows  no 
constant  variation  in  most  of  the  other  blood  diseases.  Prolonged 
coagulation  time  is  a  serious  feature  in  cases  of  pernicious  anaemia. 
There  is  often  delayed  coagulation  in  jaundice. 

While  the  amount  of  ionisable  calcium  in  the  blood  can  be  increased 
by  the  oral  administration  of  calcium  salts  and  diminished  by  the 
administration  of  citric  acid,  Addis  finds  that  the  alteration  brought 
about  is  less  than  that  necessary  to  affect  the  time  of  coagulation. 

1.  Method  of  Sahrazds  and  M'Gowan. — This  method  was  introduced 
by  Sabrazes,  and  an  almost  identical  method  was  described  independently 
by  M'Gowan  three  years  later. 

The  exact  moment  of  making  a  puncture  is  noted.  The  exuding 
blood  is  allowed  to  run  into  a  capillary  glass  tube  of  1*5  mm.  bore. 
One  end  of  the  tube  is  then  fused  in  a  flame.  This  fusion  keeps  the 
column  of  blood  steady,  and  care  must  be  taken  not  to  grasp  the  tube 
between  the  sealed  end  and  the  blood,  otherwise  the  heat  of  the  fingers 
and  consequent  expansion  of  air  would  lead  to  movement  of  the  column. 
The  tube  is  laid  flat  (preferably  in  a  chamber  kept  at  constant  tempera- 
ture), and  at  the  end  of  every  half  minute  a  file  mark  is  made  on  the 
1  Amer.  Journ.  of  Med.  Sci.,  cxlv.  1911,  p.  495. 


40  SPECIAL  METHODS   OF  EXAMINATION 

glass  tube  about  half  an  inch  from  the  end  of  the  column  of  blood, 
beginning  at  the  end  remote  from  the  sealed  portion  of  the  tube. 
Each  half  inch  is  broken  off.  The  glass  ends  are  kept  near  each  other 
and  are  then  drawn  apart.  Whenever  a  thread  of  fibrin  is  seen  between 
the  ends  the  first  stage  of  coagulation  has  occurred. 

2.  Wright's  Method. — Blood  is  drawn  into  a  series  of  tubes  of  equal 
calibre  at  definite  intervals,  and  kept  at  constant  temperature  by  means 
of  a  water  bath.  At  varying  intervals  the  observer  blows  through  the 
tubes,  and  whenever  blood  cannot  be  expelled  from  one  the  "  coagulation 
time  "  is  taken. 

3.  Buckmaster's  Method. — A  drop  of  blood  is  taken  up  with  a 
platinum  loop  and  placed  in  an  oven  with  glass  windows.  The  loop 
is  repeatedly  turned  from  the  vertical  to  the  horizontal  position  and 
vice  versd  by  means  of  a  handle  outside,  and  the  moment  when  the 
corpuscles  are  prevented  from  being  affected  by  gravity  by  the  forma- 
tion of  the  fibrin  network  is  noted. 

4.  Addis'  Method.1 — The  apparatus  is  rather  elaborate.  Its  great 
advantage  is  that  the  blood  is  kept  at  a  definite  temperature  and 
treated  in  the  same  way  throughout.  A  drop  of  blood  is  received  on 
the  end  of  a  truncated  glass  cone,  which  is  immediately  placed  in  a 
special  chamber  on  the  stage  of  a  microscope.  This  chamber  is  fitted 
with  a  thermometer  and  a  tube  with  a  nozzle,  which  discharges  a  stream 
of  mineral  lamp-oil  kept  at  uniform  temperature  and  flowing  with  uni- 
form force,  against  the  drop  of  blood.  The  nozzle  is  arranged  so  that 
it  discharges  the  oil  against  the  drop  of  blood  tangentially,  and  thus 
keeps  the  corpuscles  in  constant  movement  without  rotating  the  drop 
of  blood  as  a  whole.  The  corpuscles  stream  round  and  round  for  some 
seven  minutes  and  then  one  or  two  stationary  streaks  appear.  This 
streakiness  rapidly  spreads,  and  the  end  point  is  taken  when  there  is 
the  appearance  of  a  clot  and  the  cessation  of  movement  of  the  great 
majority  of  the  corpuscles.  The  coagulation  time  is  the  time  which 
elapses  between  the  puncture  of  the  skin  and  this  end  point. 

5.  Method  of  Lee  and    White. — By  means  of  an  all-glass  syringe 

1  c.c.  of  blood  is  withdrawn  from  a  vein  in  the  arm  and  placed  in  a 

Widal  test-tube.     The  tube  is  inverted  every  thirty  seconds.     The  end 

point  is  taken  when  the  blood  ceases  to  flow  or  change  its  contour. 

The  method  lessens  the  accelerating  effect  on  coagulation  of  contact 

with  the  tissues. 

1  Quart.  Journ.  of  Exper.  Physiology,  i.  1908,  305.     This  paper  contains  a  descrip- 
tion of  all  the  more  important  methods. 


SPECIAL  METHODS   OF  EXAMINATION  41 

6.  A  method  which  gives  fairly  accurate  results  is  simply  to  pass 
a  needle  through  a  drop  of  blood  on  a  slide  at  intervals  and  note  the 
time  when  a  thread  of  fibrin  is  first  drawn  out.    , 

7.  Another  method  is  to  put  a  drop  of  blood  on  a  slide  and  note 
when  changes  in  contour  cease  on  tilting  the  slide. 

A  quite  satisfactory  clinical  procedure  is  to  use  one  of  the  simpler 
methods  without  regard  to  temperature  and  examine  the  blood  of  a 
healthy  person  at  the  same  time,  expressing  the  result  of  the  patho- 
logical blood  as  an  index.  The  blood  must  be  obtained  in  the  same 
way  in  the  two  cases,  and  the  amount  of  contact  with  foreign  bodies 
must  be  the  same. 

The  Alkalinity  of  the  Blood. — The  estimation  of  the  alkalinity  of 
the  blood  cannot  be  said  to  yield  results  which  are  of  service  in  disease. 
The  normal  alkalinity  is  equivalent  to  about  0-3  per  cent,  of  Na2C03. 
It  is  increased  during  digestion  and  diminished  after  muscular  exercise. 
It  is  greater  in  the  early  morning  than  later. 

Practically  all  the  statements  made  regarding  the  alkalinity  of  the 
blood  in  disease  have  been  contradicted.  There  is  a  preponderance  of 
opinion  that  alkalinity  is  diminished  in  the  course  of  febrile  diseases, 
and  that  successful  antitoxin  treatment  in  diphtheria  and  other  diseases 
increases  alkalinity.  There  seems  a  certain  parallelism  between  the 
alkalinity  of  the  blood  and  the  body  resistance. 

The  results  hitherto  obtained  in  the  case  of  such  diseases  as  diabetes, 
gout,  rheumatism,  and  nephritis  are  hopelessly  discordant. 

1.  Bigler's  Method} — A  quantity  of  blood  is  placed  in  a  flask  con- 
taining 10  c.c.  of  absolute  alcohol.  The  weight  of  the  flask  before  and 
after  the  addition  of  the  blood  indicates  the  weight  of  the  blood  added. 

The  blood  coagulates  in  the  alcohol  and  is  set  aside  for  half  an  hour. 
At  the  end  of  this  time  10  c.c.  of  distilled  water  is  added,  the  mixture 
is  shaken  and  again  set  aside  for  half  an  hour.  Under  these  conditions 
the  blood  gives  an  alkaline  reaction  to  the  diluted  alcohol. 

Dilute  sulphuric  acid  is  now  added  drop  by  drop  from  a  burette, 
and  after  each  drop  the  reaction  is  tested  with  glazed  red  litmus  paper. 
"When  the  paper  ceases  to  become  blue  the  alcoholic  solution  is 
neutralised,  and  from  the  quantity  of  acid  employed  the  alkalinity  of 
the  sample  of  blood  is  ascertained. 

2.  Drouiris  Method? — Two  solutions  are  required — (a)  Solution  of 

1  Central./.  Balder.,  xxx.,  13th  December  1901. 

2  Hemoalkalimetrie,  These  de  Paris,  1892. 


42  SPECIAL  METHODS   OF  EXAMINATION 

oxalic  acid  2*1  parts  per  1000;  (b)  solution  of  sulphate  of  soda  10  parts 
per  1000.  In  a  series  of  ten  test-tubes  from  right  to  left  decreasing 
quantities  of  the  acid  solution  and  increasing  quantities  of  soda  sulphate 
are  placed.     The  volume  of  the  acid  solution  is  thus  kept  constant. 

Solution  of  oxalic  acid        .10987654321  drops. 
Solution  of  sodium  sulphate    123456789  10     „ 

Blood  is  collected  in  a  graduated  tube  and  placed  in  a  known 
volume  of  saturated  sodium  sulphate  solution  to  delay  coagulation. 
Equal  known  quantities  are  now  placed  in  each  of  the  ten  tubes. 

The  reaction  in  each  tube  is  tested  with  glazed  litmus  paper.  Those 
at  the  right  will  remain  acid;  those  at  the  left  will  be  alkaline;  between 
the  two  one  will  be  neutral. 

The  amount  of  acid  in  this  tube  indicates  the  alkalinity  of  the 
amount  of  blood  added.  The  neutral  sulphate  of  soda  does  not  affect 
the  result. 

3.  Dare's  Haemoalkalimeter.1 — This  method  is  based  upon  the  dis- 
appearance of  the  spectrum  of  oxyhemoglobin  in  the  blood  on 
neutralisation  with  a  dilute  solution  of  tartaric  acid.  The  observation 
can  be  made  with  only  a  single  drop  of  blood.  The  hsemoalkalimeter 
is  a  specially  constructed  tube. 

4.  Precipitate  Reaction  Method. — Boycott  and  Chisolm2  point  out 
that  the  colour  of  the  indicator  may  vary  materially  with  the  presence 
or  absence  of  protein.  In  the  presence  of  protein  the  end  reaction  is 
therefore  not  well  defined.  These  observers  suggest  a  precipitate 
reaction  as  a  test  for  the  degree  of  alkalinity. 

A  series  of  small  test-tubes  are  charged  with  quantities  of  N/1000 
sulphuric  acid,  increasing  by  0"1  c.c.  from  O'O  to  1*2  c.c,  the  total 
volume  of  liquid  in  each  tube  being  made  up  to  2  c.c.  with  distilled 
water.  Each  tube  then  receives  a  drop  (about  0*02  c.c.)  of  blood,  the 
contents  are  mixed,  and  the  tubes  are  placed  in  a  water  bath  at  45°  C. 
for  one  hour.  They  are  then  wiped  clean  and  examined.  The  tubes 
containing  the  smaller  amounts  of  acid  are  very  slightly  opalescent. 
Those  containing  the  larger  quantities  of  acid  show  a  flocculent  pre- 
cipitate. With  normal  blood  this  precipitate  usually  occurs  in  the 
tubes  containing  0'7  and  0'9  c.c.  of  N/1000  acid.  The  end  point  is 
the  point  half  way  between  the  first  tube  which  shows  a  precipitate, 
and  the  last  which  does  not. 

1  Bull.  Johns  Hopkins  Hospital,  xiv.  1903,  175. 

2  Biochemical  Journ.,  v.  1910,  23. 


SPECIAL  METHODS   OF  EXAMINATION  43 

A  dropping  pipette  with  an  outside  diameter  of  1'2  mm.  gives  a 
drop  of  blood  of  rather  more  than  0*02  c.c.  The  exact  volume  for  each 
experiment  is  obtained  by  weighing  5  or  10  drops  and  from  the  known 
specific  gravity.  Since  the  size  of  a  drop  of  blood  increases  as  coagula- 
tion becomes  imminent,  the  drops  should  be  distributed  quickly.  There 
is  a  difference  in  the  size  of  the  drop  which  the  same  pipette  will 
deliver  from  the  blood  of  different  individuals  even  when  all  the 
samples  show  the  same  haemoglobin  content,  but  the  variation  in  the 
case  of  blood  showing  the  same  percentage  of  haemoglobin  does  not 
exceed  O002  c.c,  so  that  for  many  purposes,  using  a  standardised 
pipette,  weighing  may  be  dispensed  with.  Knowing  the  volume  of 
the  drops,  the  amount  of  acid  required  may  be  expressed  either  in 
terms  of  a  standard  drop  of  0#02  c.c.  or  as  c.c.  of  N/10  acid  per 
100  c.c.  of  blood. 

The  end  point  is  ultimately  the  same  at  whatever  temperature 
between  15°  and  45°  C.  the  reaction  takes  place.  The  concentration 
of  the  acid  and  the  volume  are  immaterial  within  wide  limits,  but 
comparison  is  facilitated  by  keeping  them  the  same. 

The  precipitate  is  due  to  the  presence  of  some  part  of  the  formed 
elements  of  the  blood  which  does  not  go  into  solution  when  blood  is 
laked  with  distilled  water.  The  reaction  is  the  same  after  as  many 
leucocytes  as  possible  have  been  removed.  The  precipitate  is  soluble  in 
alkali  and  in  excess  of  acid.  The  presumption  is  that  the  precipitate  is 
composed  of  the  nucleo-protein  of  the  red  cells.  The  characteristic 
nocculation  is  probably  due  to  the  presence  of  stromata. 

Specific  Gravity  of  the  Blood. — (1)  Mixtures  of  glycerine  and 
water  or  solutions  of  various  salts  have  been  employed  to  provide  a 
series  of  fluids  of  different  specific  gravity.  These  are  placed  in  bottles 
and  a  drop  of  blood  is  added  until  it  is  found  that  the  blood  floats  in 
one  and  sinks  in  another.  The  intermediate  figure  gives  the  specific 
gravity  of  the  blood.  These  methods  are  unsatisfactory,  because  the 
blood  diffuses  into  an  ill-defined  cloud,  and  in  the  glycerine  mixtures 
it  soon  tends  to  sink  even  though  it  has  been  originally  lighter  than 
the  fluid. 

(2)  Hammerschlag' s  Method. — This  is  a  useful  clinical  method.  A 
mixture  of  chloroform  and  benzole  of  a  specific  gravity  of  1055-1060  is 
made.  A  drop  of  blood  is  allowed  to  fall  into  this  from  a  pipette.  If 
the  drop  sinks,  chloroform  must  be  added  to  the  mixture ;  if  the  drop 
floats,  benzole  should  be  added  and  the  mixture  stirred  with  a  glass  rod. 


44  SPECIAL  METHODS   OF  EXAMINATION 

When  the  drop  remains  suspended,  with  no  tendency  either  to  sink 
or  to  float,  the  mixture  has  the  same  specific  gravity  as  the  blood. 
The  specific  gravity  is  then  ascertained  by  means  of  a  sensitive 
hydrometer. 

(3)  Whyte's  Method.1 — Whyte  obtained  the  most  satisfactory  results 
with  a  mixture  of  oil  of  wintergreen  (i.e.  methyl-salicylate,  sp.  gr.  T180) 
and  castor  oil  (sp.  gr.  0-950).  In  this  the  blood  remains  as  a  definite 
globular  drop,  which  will  keep  floating  at  the  surface  of  a  mixture  of 
higher  specific  gravity,  and  will  definitely  sink  to  the  bottom  in  a 
mixture  of  lower  specific  gravity.  The  examination  is  rapidly  made  at 
the  patient's  bedside  if  bottles  of  the  testing  mixture  are  prepared 
beforehand  representing  the  different  specific  gravities  desired— a  plan 
which  cannot  be  carried  out  if  chloroform  and  benzole  are  employed, 
on  account  of  their  extreme  volatility. 

In  the  use  of  this  oil  mixture  two  points  must  be  noted :  in  the 
first  place,  a  drop  not  smaller  than  5  c.mm.  should  be  employed, 
as,  if  the  specific  gravities  of  the  blood  and  the  oil  do  not  differ 
greatly,  drops  smaller  than  this  will  neither  rise  nor  fall,  but,  owing 
to  the  friction  of  the  fluids,  will  remain  stationary. 

In  the  second  place,  the  heavier  ingredient  of  the  mixture  (the  oil 
of  wintergreen)  is  more  volatile  than  the  lighter,  so  that,  if  the  bottle 
is  frequently  opened,  the  specific  gravity  of  the  mixture  will  become 
appreciably  lower  after  a  few  days ;  in  any  case,  however,  a  new  supply 
of  oil  will  be  required  by  that  time  on  account  of  the  accumulation 
of  blood-drops  in  the  testing  fluid.  In  the  case  of  the  glycerine  and 
water  mixture  there  exists  the  same  need  for  a  fresh  supply  at  frequent 
intervals,  owing  to  the  increasing  turbidity  produced  by  the  repeated 
addition  of  blood-drops.  This  method  is  more  rapid  than  Hammerschlag's, 
and  is  therefore  very  useful  when  frequent  estimations  are  required. 

The  important  effect  of  temperature  upon  specific  gravity  must  be 
borne  in  mind  in  the  preparation  of  these  mixtures  for  testing  the 
blood.  The  contents  of  a  specific  gravity  bottle  may  weigh  1000 
grains  in  the  temperate  climate  of  Europe,  and  only  997  grains  during 
the  hot  season  in  the  tropics.  The  same  difference  of  specific  gravity 
will  be  shown  if  a  hydrometer  is  used. 

The  normal  specific  gravity  is  about  1055.  It  varies  in  direct 
proportion  to  the  amount  of  haemoglobin  in  the  blood. 

The  Molecular  Concentration  of  the  Blood — Cryoscopy. — This 

1  Edinburgh  thesis  (unpublished). 


SPECIAL  METHODS   OF  EXAMINATION 


45 


method  depends  upon  the  fact  that  the  freezing-point  of  water  is 
lowered  by  substances  in  solution  in  direct  proportion  to  the  number 
of  molecules  and  ions  in  solution. 

Beckmann's  cryoscope  is  most  commonly 
used.  It  consists  of  a  covered  glass  jar  (C) 
which  contains  the  freezing  mixture  and  stirrer 
{E)  which  projects  through  the  cover.  In  a 
central  aperture  in  the  cover  there  is  fixed  a 
wide  test-tube  (B).  In  this  test-tube  is  a 
cork  which  supports  the  freezing  tube  (A). 
The  freezing  tube  has  a  side  opening,  and  con- 
tains a  delicate  thermometer  (D)  and  a  stirrer 
(F)  made  of  platinum  wire. 

As  the  thermometer  has  not  a  fixed  zero, 
the  reading  which  it  gives  for  distilled  water 
must  first  be  ascertained.  The  bulb  of  the 
thermometer  is  fully  submerged  in  distilled 
water,  the  outer  chamber  is  filled  with  a 
freezing  mixture.  The  freezing  tube  may  at 
first  be  placed  in  the  freezing  mixture,  but 
after  it  has  cooled  to  near  the  freezing-point 
it  must  be  transferred  to  tube  B,  where  it 
will  be  protected  from  the  freezing  mixture 
by  a  covering  of  air.  As  the  water  gradu- 
ally cools  it  reaches  a  temperature  rather 
below  its  true  freezing-point  and  then  freezes. 
If  freezing  be  unduly  delayed  it  may  be  induced 
by  dropping  a  minute  particle  of  ice  through 
the  side  opening  of  the  freezing  chamber.  At 
the  moment  of  freezing  the  latent  heat  of  ice 
is  liberated  and  the  temperature  again  rises 
and  remains  up  for  a  short  time.  At  this 
point  the  temperature  is  taken.  The  process 
is  then  repeated  with  blood  instead  of  distilled 
water. 

Normally,  the  depression  of  the  freezing-point  by  the  substances  in 
blood  is  056°  C.  The  lowering  in  degrees  centigrade  is  expressed  by 
the  term  A. 

The  A  of  095  per  cent,  solution  of  NaCl  is  also  056°  C.  Such  a 
solution  is  isotonic  with  blood. 


Fig.  18. — Beckmann's 
Cryoscope. 

A.  Freezing  tube.  B.  Supporting 
tube.  C.  Container  for  freezing 
mixture.  D.  Thermometer.  E. 
and  F.  Stirrers. 


46  SPECIAL  METHODS   OF  EXAMINATION 

The  A  of  any  solution  may  be  expressed  in  terms  of  a  gramme-molecular 
solution  (1  grm.  x  the  molecular  weight  of  the  substance  is  dissolved  in 
100  c.c.  of  water)  by  dividing  it  by  1*87,  since  a  gramme-molecular  solution 
of  a  non-electrolyte  (a  substance  incapable  of  becoming  split  up  into  ions  in 
solution)  is  known  to  lower  the  freezing-point  1-87°  C. 

For  example,  if  the  A  of  blood  be  0'56°  C,  then 

1-87 
The  blood  therefore  contains  0-3  gramme-molecules  in  100  c.c. 

In  carrying  out  a  cryoscopic  examination  the  freezing  mixture  may 
be  ordinary  salt  and  ice,  but  for  accurate  results  the  freezing  mixture 
should  be  composed  so  that  it  is  only  slightly  colder  than  the  freezing- 
point  expected  in  the  substance  under  examination. 

Certain  salts  give  a  constant  temperature  when  mixed  with  a  smaller 
quantity  of  ice.     These  have  been  tabulated  by  Cohen. 

A  few  examples  are  : — 

C. 


Sodium  sulphate 

0-7 

Potassium  chromate 

1-0 

Potassium  sulphate 

1-5 

Potassium  nitrate 

30 

Zinc  sulphate  . 

5-0 

A  depression  of  the  freezing-point  of  blood  greater  than  O^S0  C. 
indicates  inadequate  kidney  function. 

Fragility  of  the  Red  Corpuscles. — The  resistance  of  the  red 
corpuscles  to  lysis  by  dilute  solution  of  salts  is  sometimes  a  matter  of 
some  diagnostic  significance.  The  resistance  is  definitely  lowered  in 
congenital  family  chola3mia  and  is  increased  in  obstructive  jaundice. 

Process. — The  corpuscles  should  be  washed  by  centrifuging  a  small 
quantity  of  blood  in  0'85  per  cent,  salt  solution.  A  one  per  cent,  solution 
of  salt  is  diluted  with  distilled  water  in  different  proportions,  e.g.  one  part 
with  nine  parts,  two  parts  with  eight,  three  with  seven,  and  so  on.  The 
resulting  0*9,  0*8,  0-7  and  more  dilute  solutions  are  placed  in  a  series 
of  small  test-tubes  and  a  roughly  similar  amount  of  the  suspension  of 
corpuscles  is  added  to  each.  The  tubes  are  inverted  once  or  twice  to 
mix  the  contents  and  left  for  an  hour.  Haemolysis  is  indicated  by  a  red 
tingeing  of  the  solution,  and  its  absence  is  indicated  by  a  precipitate 
of  the  corpuscles  while  the  solution  remains  colourless.  In  normal 
conditions  haemolysis  does  not  occur  with  salt  solutions  stronger  than 
04  per  cent.  It  has  been  shown  that  resistance  of  the  corpuscles  to 
hypotonic  solutions* is  not  necessarily  proportionate  to  their  resistance 


SPECIAL  METHODS   OF  EXAMINATION  47 

to  saponin  or  other  hemolytic   agents.     (See  M'Neil,  Journ.  of  Path, 
and  Bad.,  xv.  1910,  p.  56.) 

The  Total  Quantity  of  Blood  in  the  Body. — A  method  applicable  to 
the  human  subject  has  been  suggested  by  Haldane  and  Lorrain  Smith 1 — 

1.  The  percentage  oxygen  (or  carbon  monoxide)  capacity  of  the 
patient's  blood,  i.e.  the  capacity  of  100  c.c.  of  blood  for  0  or  CO,  is 
determined  by  testing  a  sample  against  standardised  ox  blood. 

2.  The  subject  under  observation  then  inhales  a  measured  volume 
of  CO.  The  percentage  saturation  of  the  blood  by  this  quantity  is 
determined  by  the  carmine  method,2  and  the  total  oxygen  (or  CO) 
capacity  is  deduced. 

Suppose  the  percentage  0  capacity  be  20  and  the  total  0  capacity 
be  600  c.c,  the  total  volume  of  blood  would  be 

600  x-^  =  3000  c.c. 

The  latter  figure  multiplied  by  the  specific  gravity  of  the  blood  will 
give  the  total  quantity  of  the  blood  in  grammes. 

Lorrain  Smith 3  has  found  that  in  chlorosis  there  is  an  increase  of 
plasma,  and  that  in  pernicious  ansemia  the  amount  varies. 

Unfortunately  in  many  cases  in  which  the  method  would  give  useful 
information  it  appears  to  be  not  without  danger. 

Bacteriological  Examination  of  the  Blood. — In  typhoid  fever 
and  certain  other  conditions  micro-organisms  may  be  found  with  fair 
frequency  in  stained  films. 

The  presence  of  organisms  is  determined  with  much  greater  certainty 
by  making  cultures.  Blood  is  withdrawn  from  a  vein  in  the  forearm. 
A  wide  area  round  the  vein  selected  should  be  scrubbed  with  soap  and 
water,  then  dried  with  a  towel,  and  afterwards  rubbed  with  methylated 
spirit  on  sterilised  wool.  Finally,  some  ether  is  poured  on  the  part  and 
allowed  to  evaporate.  The  syringe  to  be  employed  should  be  capable 
of  being  boiled,  and  its  capacity  should  be  about  10  c.c.  It  is  boiled 
with  the  needle  in  position  for  ten  minutes  in  a  1  per  cent,  solution  of 
potassium  citrate.  Two  tubes  each  containing  about  20  c.c.  of  broth 
and  two  sloped  agar  tubes  should  be  at  hand. 

1  Journ.  of  Physiology,  xxv.  1900. 

2  Journ.  of  Physiology,  xxii. 

3  Trans.  Path.  Soc.  London,  1900,  311. 


48 


SPECIAL  METHODS   OF  EXAMINATION 


A  bandage  is  wound  round  the  upper  arm  to  constrict  the  veins. 
About  1  c.c.  of  the  potassium  citrate  solution  is  drawn  into  the  syringe 
to  delay  coagulation,  the  needle  is  inserted  downwards  into  the  vein, 
and  by  very  gently  withdrawing  the  piston  blood  is  allowed  to  flow 
into  the  syringe.     At  least  5  c.c.  should  be  obtained  if  possible. 

Two  cubic  centimetres  are  placed  in  each  tube  of  broth  and  gently 
shaken  up.  A  quantum  of  the  remaining  blood  should  be  allowed  to 
trickle  over  the  surface  of  the  agar  in  the  remaining  tubes. 

For  further  procedure  a  work  on  bacteriology  must  be  consulted. 


Fig.  19. — Reichert's  Universal  Condenser. 


Dark-ground  Illumination. — By  means  of  a  reflecting  condenser 
the  direct  rays  from  the  illuminant  are  not  allowed  to  enter  the 
objective. 

The  result  is  a  brilliant  illumination  of  the  objects  on  which  the 
light  is  focussed  while  the  ground  is  kept  dark. 

The  method  brings  into  view  "  ul  tramicroscopic  "  objects  such  as  fatty 
particles  in  blood  plasma  which  are  not  made  visible  by  transmitted 
lio-ht.  Leucocyte  granules  are  clearly  demonstrated,  and  such  fine  objects 
as  the  spiroehseta  pallida  can  be  shown  without  special  preparation, 
even  with  dry  high-power  lenses.  While  the  method  does  not  super- 
sede the  use  of  stains  which  bring  out  details  depending  on  tinctorial 


SPECIAL  METHODS   OF  EXAMINATION  49 

affinities  it  is  a  valuable  adjunct  to  our  resources.  Differential  leucocyte 
counts  for  ordinary  routine  diagnosis  can  be  made  from  fresh  specimens, 
but  in  such  conditions  as  leukaemia,  where  tinctorial  distinctions  are 
essential,  the  method  is  not  available.  The  method  has  added  consider- 
ably to  our  knowledge  of  erythrocyte  structure,  and  has  demonstrated 
the  real  existence  of  objects  which  might  have  been  regarded  as  staining 
artefacts.  Different  patterns  of  reflecting  condensers  are  on  the  market. 
These  usually  take  the  form  of  either  a  sub-stage  lens  which  replaces 
the  Abbe  condenser,  or  a  plate  condenser  which  lies  on  the  stage  of 
the  microscope. 

Of  the  latter  class  Eeichert  supplies  a  very  convenient  pattern. 
Under  the  reflecting  lens  is  a  wheel  diaphragm  which  carries  a  number 
of  stops  of  different  size,  a  ground-glass  disc,  and  a  plano-convex  lens. 
The  latter,  together  with  the  reflecting  lens,  performs  the  functions  of 
an  Abbe  condenser,  so  that  by  merely  turning  the  wheel  objects  can  be 
viewed  either  by  reflected  or  transmitted  light  in  rapid  succession. 

Oil-immersion  lenses  for  use  with  reflecting  condensers  should  be 
fitted  with  a  conical  groove  to  reduce  the  numerical  aperture  to  TO. 

The  Glycogen  Reaction.1 — In  certain  conditions  many  of  the  poly- 
morphonuclear leucocytes  contain  glycogen  in  their  protoplasm.  Its 
occurrence  may  be  of  considerable  diagnostic  significance. 

The  method  is  simple.     The  following  solution  is  required : — 

Iodine  .  .  .  .  .1  grm. 

Iodide  of  potassium     ....         3  grms. 
Distilled  water  .  .  .  .     100  c.c. 

With  enough  gum  acacia  or  gum  arabic  added  to  make 
the  fluid  of  a  syrupy  consistency. 

A  large  drop  of  this  fluid  is  placed  on  a  slide,  and  a  cover-slip  bearing 
the  dry  film  to  be  examined  is  lowered  on  to  it.  After  half  a  minute 
the  cover-slip  is  pressed  down  and  the  surplus  fluid  is  wiped  off.  The 
film  is  in  this  way  fixed,  stained,  and  mounted,  and  the  preparation 
lasts  for  some  days. 

The  examination  should  be  made  with  an  oil-immersion  lens  in 
good  light,  daylight  being  preferable.  If  artificial  light  be  used  it 
should  be  as  white  as  possible,  that  from  an  incandescent  gas  burner 
being  satisfactory. 

A  film  of  normal  blood  treated  in  this  way  shows  the  red  cells 
stained  yellow  on  a  white  or  pale  yellow  background,  the  white  cells 
1  See  Gulland,  Brit.  Med.  Jonrn.,  16th  April  1904. 


50  SPECIAL  METHODS   OF  EXAMINATION" 

being  more  faintly  stained  than  the  red  corpuscles.  Lymphocytes  are 
not  readily  distinguished.  '  The  polymorphonuclears  look  darker  because 
of  their  closely-set  granules,  while  eosinophils  are  readily  recognised 
by  the  high  refractive  index  of  their  granules.  A  brown  or  reddish- 
brown  colour  may  be  seen  in  some  of  the  masses  of  blood-plates  but 
not  in  any  of  the  cells.  The  amount  of  this  extra-cellular  glycogen 
varies  greatly.  It  seems  uniformly  increased  in  diabetes,  but  in  other 
conditions  it  follows  no  ascertained  law  and  is  therefore  disregarded. 

When  the  reaction  is  "  positive "  the  change  occurs  in  the  poly- 
morphs alone,  except  in  rare  cases  of  myelocytheemia,  in  which  glycogen 
appears  in  basophils  and  myelocytes.  The  polymorphs  may  show  the 
reaction  in  three  ways — (1)  as  a  diffuse  colouration  (Plate  I.,  4) ;  (2)  as 
fine  granules  scattered  through  the  whole  or  part  of  the  cell  body 
(Plate  I.,  5,  6);  (3)  as  coarse  granules  ;or  masses  which  may  be  scattered 
throughout  the  cell  body  but  are  more  usually  found  at  or  near  the 
periphery,  sometimes  projecting  as  pseudopodia.  The  latter  are  only 
seen  when  the  reaction  is  well  marked  (Plate  I.,  7,  8).  The  granules 
are  quite  distinct  from  the  neutrophil  granules,  and  are  never  seen  in 
the  nucleus. 

The  conditions  under  which  the  reaction  occurs  are — 

1.  Severe  disturbance  of  respiration. 

2.  Antenna,  though  only  in  such  cases  that  it  is  doubtful  whether 
the  aneemia  per  se  has  anything  to  do  with  the  reaction. 

3.  Toxaemias  of  metabolic  origin  (uraemia,  chronic  morphinism, 
malignant  cachexia,  etc.). 

4.  Suppuration  and  bacterial  infection. 

Only  those  cases  of  diphtheria  which  are  associated  with  much 
inflammation  give  the  reaction.  In  typhoid  it  is  never  intense,  and 
only  appears  at  the  end  of  the  second  week.  The  chief  clinical  con- 
ditions in  which  the  reaction  is  positive  and  of  diagnostic  importance 
are  pneumonia,  empyema,  lung  gangrene,  septicaemia  and  all  advancing 
suppurative  processes,  septic  gangrene,  appendicitis,  and  peritonitis. 

It  may  be  of  use  in  distinguishing  gonorrhceal  arthritis  from 
rheumatism,  cerebral  abscess  from  cerebral  tumour,  and  in  many  such 
circumstances.     The  reaction  denotes  a  serious  condition. 

The  Oxydase  Reaction. — This  reaction  depends  on  the  oxidising 
power  of  certain  leucocytes.  Pus  or  blood  containing  numerous 
granular  leucocytes  will  bring  out  a  blue  colour  when  added  to  tincture 
of  guaiac  without  the  addition  of  peroxide  of  hydrogen.     As  the  guaiac- 


& 


' 


.  \  * 


y.^'j:':.- 


4  5 


•A     ».     •- 


Plate  I. — The  Glycogen  Reaction. 


1.  Normal  erythrocyte. 

2.  Normal  large  lymphocyte. 

3.  Normal  polymorphonuclear  neutrophil. 

4.  Diffuse  glycogen  reaction. 

5,  6.  Finely  granular  glycogen  reaction. 

7,  S.  Coarsely  granular  glycogen  reaction. 

0.  Extracellular  glycogen  and  blood-plates 


G.  L.  Q.,  fecit. 


SPECIAL  METHODS   OF  EXAMINATION  51 

blue  does  not  develop  if  the  leucocytes  have  previously  been  boiled, 
it  is  assumed  that  the  oxidising  agent  is  a  ferment.  The  microscopic 
test  depends  on  the  production. by  the  action  of  oxygen  of  an  insoluble 
dye  from  two  soluble  substances.  When  a-naphthol  and  dimethyl- 
para-phenylendiamin  are  brought  together  in  an  alkaline  medium  they 
become  oxidised  and  form  a  blue  dye-stuff,  indophenol  blue,  which  is 
precipitated.  The  presence  of  an  oxidising  agent  accelerates  the 
reaction,  and  the  oxidising  ferment  of  leucocytes  brings  it  about  with 
great  rapidity,  so  that  the  blue  dye  is  precipitated  on  their  protoplasm. 
The  reaction  is  given  by  eosinophil,  neutrophil,  and  basophil  leuco- 
cytes, and  by  myelocytes  in  marrow  and  leukemic  blood.  According 
to  Dunn  it  is  also  given  by  large  hyaline  leucocytes  in  normal  blood 
and  by  myeloblasts  of  a  late  type,  but  it  is  not  given  by  early  embryonic 
myeloblasts.  The  reaction  is  not  given  by  lymphocytes  (other  than 
large  hyaline  cells)  or  red  corpuscles.  The  only  adult  tissues  which 
give  it  are  bone-marrow  and  the  epithelium  of  the  parotid  and  lachry- 
mal glands.  Otherwise  it  is  found  only  in  granular  leucocytes  in  the 
vessels.  It  is  not  given  by  tissue  basophils  (Pappenheim  and  Nakano). 
The  reaction  is  thus  of  great  value  in  showing  the  distribution  of 
myeloid  tissue  in  foetal  organs,  and  of  myeloid  deposits  in  the  organs 
in  cases  of  leuksemia.  It  has  also  been  employed  to  assist  in  dis- 
tinguishing between  cases  of  lymphatic  (lymphocyte)  and  myeloblast 
leukaemias.  Its  significance  in  this  connection  is  discussed  in  the 
chapters  on  these  conditions. 

Process. — Fixation  by  formol,  osmic  acid  1  per  cent.,  or  alcohol,  does 
not  affect  the  reaction,  and  Dunn  has  shown  that  tissues  will  show  it 
after  they  have  been  embedded  and  cut  in  paraffin,  but  the  freezing 
method  is  usually  employed.  Blood  films  may  be  fixed  for  five  minutes 
in  formol  vapour.  There  are  several  methods  of  carrying  out  the 
actual  test. 

I.  Schultzes  Method  A— 

Solution  1.  a-naphthol,  1  grm. 

Distilled  water  100  c.c.  heated  just  to  boiling 

point. 
Liquor  potassse  1  c.c.  added  drop  by  drop. 
Solution  2.  One  per  cent,  watery  solution  of  dimethyl-para- 
phenylencliamin. 

II.  Pappenheim's  Method — 

Solution  1.  a-naphthol  1  grm. 

Absolute  alcohol  30  c.c. 


52  SPECIAL  METHODS   OF  EXAMINATION 

Distilled  water  100  c.c. 
Strong  ammonia  3  drops. 
Solution  2.  Para-phenylendiamin  1  per  cent. 

The  solutions  for  these  methods  should  not  be  new.  Films  or 
sections  are  treated  with  the  solutions  in  succession. 

III.  Schultze's  Method  B— 

Solution  1.  Two  per  cent,  watery  solution  of  ^-naphthol- 
natrium  ( =  mikrozidin,  Merck). 

Solution  2.  One  per  cent,  solution  of  dimethyl  -  para- 
phenylendiamin  hydrochloride. 

IV.  V.  Gierke's  Method— 

Solution  1.  a-naphthol  1  grm.  dissolved  in  100  c.c.  boiling 
physiological  salt  solution  and  filtered. 

Solution  2.  One  per  cent,  watery  solution  of  dimethyl-para- 
phenylendiamin. 

The  solutions  for  these  two  methods  should  be  fresh,  and  are  mixed 
before  use.     Specimens  are  treated  with  the  mixture. 

Nakano  has  recently  studied  the  different  methods,  and  finds  that 
the  eosinophil  granules  are  easily  stained  by  the  first  two,  while  the 
latter  are  preferable  for  neutrophil  cells.  The  two  latter  methods  are 
more  sensitive  and  more  labile  than  the  first  two.  Gierke's  is  the  best 
for  formol  material.  Unfixed  preparations  last  only  about  four  hours. 
Fixed  specimens  last  about  twenty-four  hours,  but  faded  specimens  can 
be  stained  again  and  again.  As  the  indophenol  is  rapidly  soluble  in 
alcohol  and  xylol,  specimens  cannot  be  mounted  in  balsam  with  the 
exception  of  those  prepared  by  Pappenheim's  method.  Dunn  recom- 
mends undiluted  water-glass  as  a  mounting  medium. 

Fatty  Degeneration  of  the  Blood  Cells. — Films  may  be  fixed  in 
formaline  vapour  for  fifteen  minutes  or  longer  and  stained  with  Sudan  III. 
or  scharlach  E.  Shattock  and  Dudgeon x  recommend  a  saturated  solu- 
tion of  scharlach  E.  in  75  per  cent,  alcohol.  After  staining,  the  films 
are  washed  in  75  per  cent,  alcohol,  then  water,  and  may  be  counter- 
stained  with  hsemalum  for  three  minutes,  washed,  and  mounted  in 
Farrant's  medium.  Fat  is  found  in  the  leucocytes  in  a  variety  of 
toxic  and  chronic  conditions.  In  diphtheria  and  pernicious  ansemia 
a  scharlach  granulation  not  quite  identical  with  fat  has  been  described. 

Vital  Staining. — Two  methods  are  available — (1)  A  dilute  solution 

1  Proc.  Boy.  Soc,  1907. 


SPECIAL  METHODS   OF  EXAMINATION  53 

of  the  stain  in  physiological  salt  solution  is  placed  on  the  skin  before 
a  puncture  is  made.  The  puncture  is  made  through  the  drop  of  stain- 
ing fluid  and  the  exuding  blood  immediately  comes  in  contact  with  it. 
Films  are  made  from  the  mixture  in  the  ordinary  way.  (2)  Cover-slips 
are  charged  with  the  stain  in  a  dry  condition.  This  is  effected  by 
applying  a  drop  of  an  alcoholic  solution  of  the  stain  (0*02  grm.  stain 
in  20  grms.  alcohol)  and  allowing  it  to  evaporate  to  dryness.  A 
prepared  cover-slip  is  charged  with  a  drop  of  blood,  a  second  clean 
cover-slip  is  dropped  upon  it,  and  after  two  or  three  minutes  the 
cover-slips  are  drawn  apart  and  the  films  are  allowed  to  dry.  The 
most  useful  stains  are  neutral  red,  azur,  and  methylene  blue. 

After  vital  staining  films  may  be  fixed  and  stained  by  other  methods. 

In  addition  to  the  granular  basophilia,  which  may  be  seen  in  red 
cells  in  certain  conditions,  the  vital  method  demonstrates  a  filamentous 
substance  and  also  metachromatic  granules  in  the  erythrocytes.  (See 
Folia  Hmmatologica,  1907,  supplement  Hefte,  1  et  seq.) 

Estimation  of  the  Calcium  Content  of  the  Blood. — This  method 
was  introduced  by  Blair  Bell,1  who  considers  that  calcium  salts  play 
an  important  part  in  connection  with  the  reproductive  functions  in 
the  female.  The  method  consists  in  the  conversion  of  the  lime  into 
calcium  oxalate  and  the  enumeration  of  the  oxalate  crystals. 

By  means  of  a  special  pipette  100  c.mm.  of  blood  are  added  to  a 
glass  capsule  containing  250  c.mm.  of  a  1  in  30  aqueous  solution  of 
oxalic  acid.  The  neck  of  the  capsule  is  then  sealed  and  the  contents 
are  thoroughly  shaken.  Thereafter  250  c.mm.  of  the  following  mixture 
are  added : — 

Acetic  acid  1  per  cent.  .  .  .95  parts. 

Glycerine       .  .  .  .  .  5     „ 

After  standing  for  ten  minutes  100  c.mm.  of  this  mixture  are  added 
to  500  c.mm.  of  distilled  water.     The  crystals  of  calcium  oxalate  in  this 
dilution  are  now  counted  by  means  of  the  hsemocytometer. 
1  Brit.  Med.  Joum.,  20th.  April  1907. 


PART    II 
THE   FORMED   ELEMENTS   OF   THE  BLOOD 

CHAPTER  VI 

THE  ERYTHROCYTES 

Ltxdee  the  microscope  a  drop  of  blood  is  seen  to  contain  numerous 
cellular  bodies — the  erythrocytes  or  red  corpuscles  and  the  leucocytes 
or  white  cells — as  well  as  certain  other  elements — the  blood-plates  and 
"  blood  dust." 

The  Erythrocytes 
(a)  Colour. — In  a  fresh  drop  of  blood  the  erythrocytes  have  a  pale 
yellow  colour  when  seen  singly  ;  masses  of  erythrocytes  appear  red. 

(&)  Size. — The  average  size  of  the  red  corpuscles  is  0*0075  mm. 
(7*5  micromillimetres  or  /x).  The  size  shows  very  little  variation  in 
health.  The  average  size,  however,  is  considerably  reduced  in  the 
case  of  the  inhabitants  of  high  altitudes. 

Pathological  Variations. — In  all  anaemic  conditions  of  any  severity 
the  corpuscles  show  inequality  of  size  (anisocytosis).  Usually  the 
average  diameter  is  diminished,  but  in  pernicious  anaemia  a  large 
number  of  specially  large  cells  (megalocytes)  appear,  consequently 
the  average  size  is  increased. 

(c)  Shape. — In  man  and  all  other  mammals  except  the  Cameliclce 
(which  have  oval  and  biconvex  corpuscles)  the  erythrocytes  appear 
in  ordinary  preparations  as  biconcave  discs.  The  centre  of  each  disc 
shows  a  clear  area,  which  is  very  conspicuous  in  stained  specimens. 
Its  proportion  to  the  rest  of  the  cell  is  an  important  guide  in  the 
estimation  of  the  severity  of  amemic  conditions. 

Weidenreich1  maintains  that  the  red  blood  corpuscles  of  mammals  are  bell- 
shaped  and  not  biconcave  until  deformed  by  extraneous  influences.  This 
observation  is  supported  by  Lewis,2  who  finds  that  the  corpuscles  as  seen  in 

1  Weidenreich,  Arch.f.  mibr.  Anat.,  Bd.  lxi.  1902,  459. 

2  Lewis,  Journ.  of  Mai  Research,  January  1904.     See  also  Orsos,  Folia  Hcemato- 
■i,  vii.  1909,  1. 


THE   EEYTHROCYTES  55 

the  omentum  of  a  live  guinea-pig  are  either  deep  or  shallow  cups  and  never 
biconcave.  The  same  is  said  to  be  true  of  human  blood  examined  on  a  warm 
stage.  So  far  as  our  observations  go  we  are  unable  to  accept  Weidenreich's 
view  in  its  entirety.  There  is  no  doubt  that  in  practically  all  blood  prepara- 
tions a  certain  number  of  the  corpuscles  appear  to  have  the  bell  shape  indi- 
cated by  Weidenreich.  Whether  these  cells  are  normal  or  distorted  we  are 
unable  to  say,  but  their  proportion  does  not  increase  to  the  extent  we  would 
expect  if  Weidenreich's  view  were  correct,  when  special  precautions  regarding 
osmosis  and  temperature  are  taken. 

Effects  of  Osmosis. — The  red  corpuscles  are  extremely  susceptible  to 
changes  in  the  salt  content  of  the  plasma.  Concentration  of  the  plasma 
from  the  addition  of  salts  or  the  evaporation  of  fluid  leads  to  shrivelling 
of  the  corpuscles.  The  outline  becomes  jagged  and  irregular,  and  such 
corpuscles  are  said  to  be  crenated.  This  appearance  is  very  commonly 
seen  near  the  edge  of  blood  preparations  examined  in  the  fresh  state. 

Dilution  of  the  plasma  causes  the  corpuscles  to  swell  up  and  become 
rounded,  and  if  the  dilution  be  carried  too  far  the  corpuscle  ruptures 
and  the  haemoglobin  passes  into  solution.  The  blood  is  then  said  to 
be  "  laked." 

Heat. — If  a  drop  of  blood  be  heated  the  red  corpuscles  are  broken 
up  as  if  by  explosion.  Globules  of  haemoglobin  separate  out,  and  these 
are  often  connected  with  the  corpuscles  by  long  narrow  processes. 

Pathological  Alterations  in  Shape. — Apart  from  mere  mechanical  dis- 
tortion such  as  indentation,  variation  in  the  shape  of  the  red  corpuscles 
is  only  seen  in  anaemic  conditions.  In  anaemia  many  of  the  corpuscles 
may  be  oval,  sausage-shaped,  pear-shaped,  tailed,  or  quite  irregular  in 
shape.  This  condition  is  termed  poikilocytosis.  The  amount  of  poikilo- 
cytosis  is  usually  proportional  to  the  degree  of  anaemia,  but  it  should 
be  kept  in  mind  that  in  pernicious  anaemia  poikilocytosis  is  generally 
apparently  much  more  marked  than  in  other  anaemias  of  a  similar 
degree,  because  of  the  combination  with  anisocytosis.  Occasional 
cases  are  met  with  in  which  there  is  but  little  poikilocytosis. 

(cl)  Structure. — The  erythrocytes  are  soft,  friable,  and  elastic.  They 
are  surrounded  by  a  fine  elastic  membrane,  and  consist  of  haemoglobin 
in  a  loose  scanty  reticulum,  which  can  be  demonstrated  by  vital  staining, 
and  which  is  easily  seen  in  young  cells  before  their  haemoglobin  comple- 
ment is  complete.  The  erythrocytes  have  a  special  affinity  for  acid 
dyes,  and  in  health  stain  but  feebly  with  basic  stains. 

Polychromatophilia. — In  certain  circumstances  the  red  corpuscles 
may   show   an   unusual   affinity   for   basic   dye's.      This   is   known   as 


56  THE  EKYTHROCYTES 

polychromatophilia  or  polychromasia.     At  least   four  different  appear- 
ances may  be  distinguished. 

1.  Diffuse  Polychromasia. — Two  degrees  of  this  condition  may  be 
recognised — (a)  The  red  corpuscles  may  show  a  purple  colour  when 
stained  with  eosine-methylene  blue  mixtures ;  with  Ehrlich's  stain 
they  appear  brown.  This  condition  is  readily  seen  in  foetal  blood,  in 
experimental  anaemia,  and  in  the  course  of  recovery  or  remission  in 
simple  and  pernicious  anaemias.  It  is  specially  common  in  megalo- 
blasts,  rather  le^ss  so  in  normoblasts  (Plate  II.,  b).  (b)  When  stained 
with  eosine-methylene  blue  mixtures  the  corpuscles  show  a  brownish 
tinge.  This  is  seen  in  late  foetal  blood  and  in  the  course  of  recovery 
from  anaemia  (Plate  II.,  c). 

Both  types  are  to  be  regarded  as  regenerative,  and  probably  indicate 
stages  in  the  formation  or  ripening  of  haemoglobin,  the  first  type  repre- 
senting an  early  and  the  second  a  later  stage  of  the  process. 

2.  Granular  Polychromasia — Punctate  Basophilia. — This  condition  is 
best  seen  with  eosine-methylene  blue  mixtures.  Only  a  small  propor- 
tion of  the  cells  show  it.  It  is  a  special  feature  of  the  blood  in  lead 
poisoning,  in  which  it  is  more  constant  than  in  any  other  condition. 
It  also  occurs  in  pernicious  anaemia,  acute  lymphatic  leukaemia,  grave 
secondary  anaemias  of  any  origin,  especially  those  due  to  haemorrhage 
and  to  septic  poisoning.  It  may  occasionally  be  found  in  various  toxic 
conditions,  especially  in  chronic  intestinal  catarrh. 

The  granules  vary  greatly  in  their  incidence  in  the  individual  cell 
and  in  size ;  they  may  be  scanty  or  the  cell  may  be  stippled  all  over. 

The  condition  is  often  seen  in  normoblasts  and  megaloblasts.  It  is 
found  in  cells  with  the  nucleus  intact  and  in  cells  with  dividing  nuclei. 
These  facts  seem  to  indicate  that  the  granules  are  plasmatic  and  not 
nuclear.  The  granules  do  not  stain  with  methyl  green,  and  are  there- 
fore not  of  the  nature  of  chromatin.  They  have  been  described  as 
occurring  in  bone-marrow  and  in  the  blood  of  new-born  infants,  and 
these  facts  have  been  taken  as  suggesting  that  the  granules  indicate 
blood  regeneration.  This  view  in  simple  form  we  are  unable  to  accept. 
The  stippling  appears  to  us  to  resemble  closely  those  degenerative 
granules  which  occur  in  the  red  cells  after  poisoning  with  phenyl- 
hydrazin  and  which  are  undoubtedly  degenerative.  In  clinical  work 
we  find  that  granular  red  cells  appear  in  greater  numbers  in  propor- 
tion to  the  severity  of  toxic  symptoms,  and  we  look  upon  them  as  the 
expression  of  a  degenerative  change  in  the  corpuscle.  It  is  probable 
that  the  cells  showing  the  granules  are  young  forms,  but  the  stippling  is 


Plate  II. — Polychromatophilia. 

Blood  film  from  a  rabbit  three  days  after  injection  with 
phenyl-hydrazin  (eosine  and  methylene  blue). 

a.  Red  corpuscle  showing  degenerated  portions. 

6.  Diffuse  polychromasia. 

c.  Diffuse  polychromasia  (riper  haemoglobin). 

d.  Some  diffuse  polychromasia  and  granular  basophilia  (a  poisoned 

young  cell). 

e.  Red  corpuscle  showing  granular  basophilia,  a  "Cabot's  ring" 

and  a  "Jolly  body." 
/.    Megaloblast  showing  granular  basophilia. 
g.  Polychromasic  megaloblast. 
A.   Megaloblast. 
I:   Normoblast. 


A.  G. ,  fecit. 


THE   EEYTHEOCYTES  57 

to  be  regarded  as  an  indication  of  pathological  alteration  rather  than  of 
mere  youth  (Plate  II.,  d). 

3.  Nuclear  Particles. — Eed  corpuscles  showing  one  or  more  basophil 
points  are  occasionally  seen  in  the  blood.  They  are  most  frequently 
seen  in  conditions  in  which  nucleated  cells  are  present.  These  particles 
stain  with  methyl  green  and  are  derived  from  chromatin.  They  have 
been  called  Howell's  bodies  and  Jolly  bodies.  The  ring-shaped  bodies 
described  by  Cabot  as  occurring  in  the  blood  in  pernicious  anasmia  are 
probably  of  the  same  nature.  These  are  found  either  singly  or  inter- 
woven with  others,  and  measure  from  2  to  8  p  in  diameter,  and  are 
regarded  by  Cabot  as  being  connected  with  the  former  nucleus  of 
the  cell  (Plate  II.,  e). 

4.  The  reticular  substance,  which  can  be  demonstrated  by  vital 
staining,  differs  from  the  foregoing  types  pi  polychromasia.  Indeed 
punctate  basophilia,  Jolly  bodies,  and  reticular  substance  can  be 
demonstrated  in  the  same  corpuscle.  The  reticular  substance  is  found 
normally  in  one  or  two  per  cent,  of  the  erythrocytes.  Cells  showing  it 
are  more  abundant  in  the  blood  of  the  bone-marrow  and  in  the  blood  of 
new-born  subjects.  The  reticular  cells  are  increased  after  haemorrhage 
and  are  present  in  antennas.  The  reticulum  is  plasmatic  in  nature, 
and  its  presence  in  many  cells  probably  indicates  regeneration  of  the 
blood. 

Polychromasia,  basophil  stippling,  and  reticular  substance  may  all 
be  regarded  as  different  morphological  aspects  of  the  same  thing — the 
basophil  substance  of  young  erythrocytes,  but  the  stippling  is  an  aspect 
seen  only  in  pathological  conditions. 

V.  Schilling-Torgau l  has  recently  published  an  important  account  of  his 
researches  on  the  structure  of  the  erythrocytes.  He  points  out  that  in  the 
peripheral  blood  there  are  corpuscles  varying  in  age  from  one  to  twenty  days 
and  that  their  structure  may  vary  accordingly.  He  has  studied  the  erythro- 
cytes by  a  variety  of  methods,  including  the  use  of  dark-ground  illumination, 
vital  staining,  different  fixatives,  and  after  different  degrees  of  haemolysis. 

He  regards  the  young  adult  corpuscles  as  slightly  saucer-shaped  with 
a  thickened  edge.  The  biconcave  disc-forms  with  a  deep  hollow  on  either 
side  are  just  as  much  artefacts  as  the  bell-shaped  corpuscles  described  by 
Weidenreich. 

In  the  typical  fully-formed  erythrocyte  the  following  parts  are  recognised. 

(a)  A  nucleus  or  nuclear  rest  which  by  a  process  of  physiological  meta- 
morphosis has  become  a  blood-plate. 

(b)  Protoplasm  consisting  of  a  stroma  containing  haemoglobin,  an  endo- 
plasmic capsule  or  crust,  and  an  exoplasmic  cell  membrane. 

1  Folia  Hcematologica,  xiv.  Archiv,  1912,  p.  95  ;  Centralb.  f.  Bacteriol,  lxiii.  p.  400. 


58 


THE  ERYTHROCYTES 


(c)  Archoplasm   consisting   of    a    glassy   body,    a   capsule   corpuscle, 
centriole  and  scattered  granules. 


Bl-Pl. 


Figs.  20  and  21. — Composite  Scheme  op  Structure  op  Erythrocyte  (Schilling- 
Torgau).  The  various  structures  shown  could  not  all  be  demonstrated 
at  once  in  the  same  corpuscle  or  by  any  one  method.  for  illustrations 
of  actual  preparations  the  original  papers  should  be  consulted.  (re- 
procluced  from  the  "Folia  Hcematologica"  by  land  permission  of  the  author.) 


M.  Membrane. 

R.   Space  between  M.  and  H. 
H.  Ha-moglobin-containing  part. 
G.   Glassy  body. 


Bl.-Pl.  Blood-plate  (nucleus). 
K.  Capsule  corpuscle, 
ft    Centriole. 

St.  Ground  structure  with  basophilic  protoplasmic 
substance. 


The  Blood-Plate. — The  nucleus  of  the  red  cell  is  like  that  of  other  cells 
only  in  its  early  life  history.     At  a  later  stage  the  blood-plate  represents  the 


THE   ERYTHROCYTES  59 

erythroblast  nucleus.  It  arises  by  a  process  of  physiological  modification, 
possibly  mitosis.  The  plate  remains  in  an  eccentric  position  within  the 
erythrocyte  but  is  easily  extruded  and  destroyed.  Plates  do  not  pre-exist 
free,  but  they  may  be  extruded  and  become  a  third  formed  element  of  the 
blood  in  the  process  of  making  preparations.  An  abrupt  change  in  structure 
similar  to  that  from  nucleus  to  plate  occurs  in  the  derivation  of  spermatozoa 
from  spermatids. 

It  is  well  known  that  the  erythroblast  nucleus  is  easily  extruded,  but  this 
only  occurs  in  extreme  pathological  conditions  and  in  the  embryo.  It  is 
always  rare,  and  after  sufficiently  rapid  fixation  is  hardly  ever  seen. 

Any  evidence  of  intracellular  solution  of  the  nucleus  is  to  be  regarded  as 
due  to  bad  staining. 

The  alleged  disappearance  of  the  nucleus  by  breaking  down  (karyorrhexis) 
is  either  a  pathological  process  or  is  quite  undemonstrable. 

The  nucleus  disappears  without  any  visible  sign  in  multitudes  of  young 
erythrocytes. 

"Nuclear  rests"  such  as  Howell-Jolly  bodies  are  the  result  of  patho- 
logical karyolysis.  The  blue  spherules  which  may  be  seen  single  or  double 
in  severe  anaemia  are  in  part  aggregations  of  the  basophil  protoplasmic- 
substance,  and  their  partial  origin  from  nucleoli  is  not  impossible. 

Stroma. — There  is  a  protoplasmic  stroma,  probably  somewhat  radially 
arranged  and  seldom  visible.         •--\ 

It  lies  like  a  cap  round  the  archoplasm,  with  its  chief  mass  towards  the 
convexity  of  the  cell.  This  stroma  contains  haemoglobin.  In  young  cells 
this  stroma  constitutes  the  network  seen  in  vital  staining,  the  basic  substance 
which  shows  as  polychromasia,  and  it  may  appear  as  basophilic  stippling  in 
pathological  conditions.  In  riper  cells  it  forms  the  Schuffher's  dots  which  are 
seen  in  malaria.  The  haemoglobin-containing  portion  is  separated  off  in  a 
cap  or  ring-like  periphery  in  young  and  anaemic  cells,  so  that  there  is  an 
achromatic  central  part.  In  ripe  cells  a  homogeneous  saturation  of  all  parts 
with  haemoglobin  is  perhaps  possible. 

The  Endoplasmic  Capsule. — The  protoplasmic  substance  is  thickened  at  the 
periphery  into  a  surrounding  crust,  while  the  inner  portion  is  more  fluid. 
This  crust  constitutes  the  cholesterin-lecithin  membrane  of  Weiclenreich. 

The  Cell  Membrane. — The  erythrocyte  possesses  a  delicate  outer  membrane 
of  exoplasm. 

"  Shadow  corpuscles "  are  essentially  haemolysed  stromata  separated  in 
layers  and  are  not  exclusively  exoplasmic  vesicles  or  membranes. 

The  Glassy  Body. — Artificial  and  pathological  alterations  of  the  erythro- 
cytes reveal  a  sharply  circumscribed  achromatic  (haemoglobin-free)  substance. 

Its  appearance,  isolation,  and  position  in  the  erythrocyte  mark  it  off  as  a 
special  structure— the  glassy  body.  This  is  to  be  regarded  as  "  rest "  material 
corresponding  to  the  large  clear  area  which  is  seen  round  the  nucleus  in 
leucocytes  and  connective-tissue  cells,  and  which  provides  the  achromatic 
spindle  in  mitosis.  It  corresponds  in  extent  to  the  central  clear  area  seen  in 
erythrocytes  prepared  in  the  ordinary  way.  The  glassy  body  is  essentially 
different  from  the  nucleus  and  its  rests  and  from  "  nucleoids." 

It  may  be  demonstrated  by  vital  staining,  by  the  dark-ground  illumina- 


60  THE  ERYTHROCYTES 

tion  combined  with  vital  staining,  by  rapid  fixation  of  corpuscles  by  allowing 
blood  to  flow  into  perchloricle  of  mercury  or  osmic  acid,  but  best  of  all  by 
a  special  technique  following  fixation  by  Dominici's  iodine  and  perchloride 
mixture. 

A  definite  grade  of  fixation  is  necessary  to  make  the  glassy  body  visible. 
Too  complete  fixing  makes  the  bodies  just  as  invisible  as  they  become  when 
ordinary  methods  are  employed.  They  appear  in  such  circumstances  as  the 
clear  central  portions. 

The  glassy  body  can  be  thrown  out  of  the  cell  without  noteworthy 
change  in  the  haemoglobin-containing  portion. 

This  leads  to  the  question  whether  the  glassy  bodies  are  still  present  in 
the  ordinary  erythrocytes  of  films,  and  whether  they  cause  the  bell  shape 
of  the  erythrocyte.  It  is  possible  in  thick  films  which  have  been  de-haemo- 
globinised  by  Manson's  method  to  demonstrate  circular  and  oval  bodies  in 
the  haemolysed  corpuscles  independent  of  the  central  clear  area.  The  form 
of  the  erythrocyte  has  nothing  to  do  with  the  glassy  body.  In  ordinary 
circumstances  the  glassy  body  is  too  closely  bound  up  with  the  structure  of 
the  erythrocyte  to  be  noticed  independently  of  it,  and  it  lies  quite  in  the 
centre  of  the  saucer-  or  bell-shaped  corpuscle. 

Half -Moon  and  Sickle  Corpuscles. — These  bodies  are  usually  seen  as  pale, 
greatly  enlarged  erythrocytes  (15-50  fi)  which  apparently  because  of  an 
eccentric  vacuole  have  a  sharp  sickle-form.  They  are  due  to  a  swelling  of 
the  glassy  body  so  that  the  endoplasmic  capsule  of  the  cle-haemoglobinisecl 
corpuscle  is  compressed  to  one  side.  They  are  only  produced  during  the 
process  of  observation,  but  anaemia  makes  the  conditions  for  their  production 
easy  in  certain  erythrocytes. 

They  are  not  specific  for  anaemia,  but  a  special  variety  is  specific  for 
malaria.  The  stroma  may  be  pushed  to  one  side  or  spread  out  like  a  ring 
round  the  erythrocyte  and  appear  as  Schuffher's  dots. 

Capsule  Corpuscle. — This  is  a  body  so  called  because  of  its  resemblance  in 
preparations  made  by  vital  staining  to  the  cap  of  a  champagne  bottle.  It 
lies  eccentrically  in  the  neighbourhood  of  the  clear  area.  These  capsules  are 
identical  with  Arnold's  nucleoids,  Schmauch's  bodies,  Heinz's  corpuscles, 
haemoglobinogenous  bodies,  pseudo-nuclei,  pseudo-parasites,  etc.  They  appar- 
ently arise  within  the  perinuclear  area  in  young  cells  and  remain  within  the 
cell  after  the  extrusion  of  the  nucleus.  They  are  to  be  distinguished  from 
nuclear  rests  (Jolly  bodies,  etc.). 

Centriole. — This  consists  of  a  group  of  two  or  more  sharply-defined  bodies 
which  lie  in  a  soft  connecting  substance  which  may  show  a  vacuole.  This 
central  group  lies  in  close  relationship  to  the  capsule  body,  but  it  may  become 
displaced.  Both  capsule  and  centriole  are  surrounded  by  the  clear  substance 
of  the  glassy  body. 

Scattered  Granules. — There  are  granular  bodies  (Meves'  plastokonten,  etc.) 
which  may  sometimes  be  seen  in  the  region  of  the  archoplasm  or  occasionally 
scattered  throughout  the  cell.     The  nature  of  these  is  not  yet  understood. 

(e)  Rouleau  Formation.1 — When  blood  is  shed  the  red  cells  run 
1  Literature.     See  Wiltshire,  Journ.  of  Path,  and  Bad.,  xvii.  1913,  p.  282. 


THE   EEYTHEOCYTES  61 

together  to  form  long  rows,  each  cell  fitting  into  the  concavity  of  its 
neighbour. 

In  many  anasmic  conditions  rouleaux  formation  is  deficient.  This 
is  probably  due  to  the  accompanying  poikilocytosis.  In  making  films 
the  spreading  should  be  completed  before  rouleaux  formation  has  begun. 

(/)  Numbers. — In  healthy  males  the  average  number  of  erythrocytes 
is  5,000,000  per  c.mm.,  in  females  4,500,000  per  c.mm.  Counts  of  over 
6,000,000  in  healthy  persons  have  been  reported,  but  these  are  rare, 
and  most  counts  above  5,000,000,  when  not  due  to  some  obvious  cause, 
are  generally  to  be  accounted  for  by  some  slight  congestion  or  other 
circulatory  disturbance,  it  may  be  of  a  trifling  nature. 

Physiological  Variations  in  the  Number  of  the  Erythrocytes 

1.  Increase — Polycythemia. — (a)  Infancy. — The  number  of  red  cells 
is  above  the  average  in  the  new-born.  This  is  probably  due  to  the 
rapid  loss  of  fluid  by  the  pulmonary  and  skin  surfaces  after  birth. 

The  maximum  counts  are  obtained  on  the  second  or  third  day,  and 
about  the  end  of  a  week  the  count  is  like  the  adult  average. 

(b)  Race. — Eace  has  little  influence.  M'Cay1  found  a  slight  excess 
in  Bengalis  over  the  counts  in  a  number  of  Europeans  resident  in 
India. 

(c)  Vasomotor  Influences. — High  counts  are  usually  obtained  after 
the  application  of  cold,  etc.,  due  either  to  a  diminished  dilution  of  the 
blood  by  plasma  from  the  subcutaneous  tissue,  or  to  a  degree  of  localised 
stasis  in  the  circulation.  Blood  drawn  from  a  cold  finger  contains 
a  larger  number  of  red  corpuscles  than  that  from  the  same  finger 
after  it  has  been  warmed.  We  have  found  that  the  red  counts  in 
an  open-air  sanatorium  tend  to  be  above  the  average,  and  especially 
so  in  winter. 

(d)  Altitudes. — A  series  of  records  by  different  observers  shows  that 
a  definite  increase  occurs  in  persons  living  at  high  altitudes,  and  that 
the  increase  is   proportional  to   the   height.     Thus  Viault  gives   the.- 
number  for  the  Cordilleras  as  8,000,000  per  c.mm.     The  increase  soon 
disappears  when  inhabitants  of  high  altitudes  migrate  to  lower  regions. 

The   explanation   of   the   increased   number   of    corpuscles   is   not 

generally  agreed  upon.     It  has  been  held  to  be  merely  an  apparent 

augmentation   due  to  more  rapid  evaporation  of  sweat.     In  view  of 

the  fact,  however,  that  the  corpuscles  are  smaller  than  normal,  the 

1  M'Cay,  Indian  Med.  Gaz..  October  1907. 


62  THE   ERYTHROCYTES 

probability  is  that  the  increased  number  is  simply  a  means  of  present- 
ing a  larger  surface  of  haemoglobin  to  an  atmosphere  with  diminished 
pressure  of  oxygen.  There  is  no  corresponding  increase  in  the  amount 
of  haemoglobin,  and  thus  the  condition  seems  to  be  one  of  altered 
activity  rather  than  of  increased  activity  on  the  part  of  the  bone- 
marrow. 

2.  Decrease  —  Oligocythemia.  —  Physiological  diminution  in  the 
number  of  red  cells  practically  does  not  occur. 

Such  conditions  as  normal  menstruation,  pregnancy,  and  lactation 
hardly  affect  the  red  cells. 

By  keeping  animals  in  an  atmosphere  of  compressed  air  a  diminution 
of  corpuscles  has  been  brought  about.1 

Pathological  Variations  in  the  Number  of  Erythrocytes 

1.  Increase. — (a)  Mechanical. — An  apparent  increase  may  result  from 
concentration  of  the  blood  caused  by  acute  diarrhoea,  profuse  sweating, 
vomiting,  and  polyuria. 

(b)  In  congenital  heart  disease  an  increase  of  red  cells  is  common. 

(c)  In  acquired  valvular  disease  high  counts  are  occasionally  met 
with  (see  Chap.  XXXV.). 

(d)  Toxic  Conditions. — A  few  excessively  high  counts  have  been 
recorded  in  diabetes.  In  coal-gas  poisoning  and  in  poisoning  by 
benzine  compounds  there  may  be  an  increase  of  reel  cells. 

(e)  Splenomegalic  Polycythemia  {Polycythemia  Myelopathica)  {Ery- 
thremia}).— A  very  definite  increase  in  the  number  of  erythrocytes 
occurs  in  this  condition. 

2.  Diminution  in  the  Number  of  Erythrocytes  —  Oligocythemia. — 
The  causes  of  oligocythemia  are  exceedingly  numerous.  They  include 
haemorrhage,  blood  destruction  by  parasites  or  toxins,  infective  con- 
ditions, malnutrition,  and  disease  of  the  bone-marrow.  They  will  be 
discussed  under  these  headings. 

Nucleated  Red  Cells,  Normoblasts,  Megaloblasts,  Microblasts 

Nucleated  red  cells  do  not  normally  occur  in  healthy  adult  circulat- 
ing blood.  While  the  occasional  finding  of  a  nucleated  red  cell  in 
blood  otherwise  healthy  would  indicate  an  "  accident "  of  no  great 
importance,  the  presence  of  nucleated  red  cells  in  the  blood-stream  in 
even  moderate  numbers  denotes  a  serious  condition. 

1  Doyen  et  Morel,  Lyon  Medical,  21st  July  1902. 


THE   EEYTHEOCYTES  63 

The  nucleated  red  cells  are  found  normally  in  the  bone-marrow. 
There  are  two  chief  varieties — normoblasts  and  megaloblasts — and  two 
types  of  minor  importance — microblasts  and  intermediate  forms. 

1.  Normoblasts. — Normoblasts  are  of  the  same  size  as  the  ordinary 
erythrocytes,  or  may  be  slightly  larger.  They  are  round  in  shape,  and 
their  protoplasm  consists  of  haemoglobin  in  a  fine  reticulum.  The 
nucleus  is  generally  rounded,  and  measures  about  4  \i.  in  diameter. 

It  consists  of  a  nuclear  membrane  and  thick,  densely  -  packed 
chromatin,  which  may  appear  almost  solid,  but  has  an  irregularly 
radial  arrangement. 

All  degrees  of  karyorrhexis,  from  mere  budding  of  the  nucleus  to 
actual  fragmentation,  are  commonly  seen  in  circulating  normoblasts. 

Normoblasts  can  readily  be  found  in  the  blood  of  infants  for  some 
hours  after  birth.  They  rapidly  diminish  in  number,  and  are  not 
usually  found  after  a  week. 

2.  Megaloblasts. — These  are  cells  whose  average  diameter  is  much 
greater  than  that  of  the  normoblasts.  Their  diameter  may  exceed 
20  p.  The  essential  difference,  however,  is  not  that  of  mere  size.  Thus 
a  nucleated  red  cell  whose  diameter  exceeded  8  ^  might  almost  certainly 
be  classed  as  a  megaloblast,  but  a  cell  smaller  than  a  typical  normoblast 
might  yet  be  a  megaloblast.  The  criterion  is  nuclear  structure.  The 
nucleus  is  larger,  in  proportion  to  the  rest  of  the  cell,  than  that  of  the 
normoblast.  The  nuclear  diameter  may  reach  10  /x.  The  chromatin 
strands  are  much  more  widely  separated,  hence  the  nucleus  never  appears 
so  deeply  stained  as  that  of  the  normoblast,  unless  it  is  degenerated 
and  pyknotic.  Many  of  the  chromatin  particles  show  metachromatic 
staining  though  true  nucleoli  have  not  been  demonstrated. 

The  cytoplasm  does  not  differ  from  that  of  the  normoblasts.  Poly- 
chromasia  and  granular  degeneration  are  more  common  in  nucleated 
than  in  non-nucleated  red  cells,  and  more  common  in  megaloblasts  than 
in  normoblasts. 

3.  Microblasts. — These  are  nucleated  red  cells  smaller  than  normo- 
blasts. They  are  cells  which  have  either  been  abnormally  small  from 
the  first  or  are  megaloblasts  or  normoblasts  which  have  lost  part  of 
their  cytoplasm.  The  nucleus  may  be  of  either  normoblast  or  megalo- 
blast type. 

4.  Intermediate  Cells. — In  some  nucleated  red  cells  the  nuclear 
structure  is  not  so  dense  as  that  of  the  normoblast  or  so  open  as  that 
of  the  megaloblast.  They  may  be  classed  with  the  type  of  cell  they 
most  closely  resemble. 


64  THE  EKYTHEOCYTES 

The  Significance  of  Nucleated  Red  Cells  in  the  Circulation. — The 
megaloblast  is  ontogenetically  an  older  cell  than  the  normoblast.  It  is 
the  nucleated  red  cell  of  the  foetus.  It  persists  in  the  bone-marrow,  but 
ceases  directly  to  supply  erythrocytes  (or  rather  megalocytes)  to  the 
circulation.  It  gives  rise  to  normoblasts,  which  become  overwhelmingly 
more  numerous  in  the  post-natal  marrow  and  supply  the  blood  with 
erythrocytes  (see  ILematogenesis,  Chap.  XIII.). 

Any  ordinary  demand  for  an  extra  supply  of  blood-cells  is  met 
by  increased  normoblastic  proliferation.  This  proliferation  causes  a 
disturbance  of  the  bone-marrow  circulation,  so  that  a  varying  number 
of  normoblasts  may  appear  in  the  peripheral  blood. 

On  the  other  hand,  any  toxin  or  hemolytic  agent  which  not  merely 
affects  or  is  fixed  by  the  circulating  blood-cells,  but  attacks  the  bone- 
marrow,  leads  to  a  proliferation  of  megaloblasts,  consequently  megalo- 
blasts  and  their  non-nucleated  descendants,  megalocytes,  as  well  as 
normoblasts  and  normocytes,  may  appear  in  the  blood.  Megaloblasts, 
indeed,  may  outnumber  normoblasts  in  the  circulating  blood.  A 
megaloblastic  anaemia  is  thus  a  much  more  serious  condition  than  a 
normoblastic  anaemia.  In  megaloblastic  anaemia  we  may  consider  that 
not  merely  the  blood  but  the  marrow  is  affected,  and  owing  to  the 
greater  average  size  of  the  megaloblasts  their  appearance  in  the 
circulation  indicates  a  correspondingly  greater  disturbance  of  the 
bone-marrow  reticulum. 

Conditions  causing  the  Appearance  of  Normoblasts  in  the  Circulation. 
— Haemorrhage;  secondary  anaemia;  chlorosis  (rarely);  pernicious 
anaemia;  leukaemia. 

Conditions  causing  the  Appearance  of  Megaloblasts  in  Addition  to 
Normoblasts  in  the  Circulation. — Pernicious  anaemia;  bothriocephalus 
aneemia;  leukaemia;  anaemias  of  childhood;  experimental  haemolytie 
agents — phenyl-hydrazin,  toluylen-diamine,  etc. 


CHAPTER  VII 

THE   LEUCOCYTES 

Seen  in  fresh  blood,  the  leucocytes  are  colourless,  highly  refractile  cells 
presenting  differences  in  size,  in  the  shape  of  their  nuclei,  and  in  the 
characters  of  their  protoplasm. 

Numbers. — The  average  number  of  leucocytes  in  health  is  about 
7000  per  c.mm.  The  physiological  variations  may  be  stated  as  between 
5500  and  9000  per  c.mm.  The  proportion  of  white  to  reel  cells  is  about 
1  to  700. 

Classification. — The  finer  structure  of  the  leucocytes  and  their 
different  characters  can  only  be  made  out  in  stained  films.  They  are 
classified  according  to  their  size,  the  shape  of  the  nucleus,  the  presence 
or  absence  of  granules  in  their  protoplasm,  and  the  staining  reactions 
of  those  granules.  All  varieties  have  a  well-developed  double  centro- 
some  and  well-marked  nucleoli. 

The  following  are  found  in  the  circulating  blood : — 

1.  Polymorphonuclear  Neutrophil  Leucocytes. — These  cells  vary  con- 
siderably in  size ;  their  average  diameter  is  about  11  p.  The  nucleus 
is  lobulated,  the  different  parts  being  united  by  strands  of  chromatin. 
The  number  of  lobules,  their  size,  and  their  arrangement  vary  very 
greatly.  The  protoplasm  consists  of  a  groundwork  and  numerous 
granules.  The  groundwork  has  a  very  slight  affinity  for  stains,  but 
will  fix  a  certain  amount  of  acid  dye.  The  granules  are  best  demon- 
strated after  fixing  and  staining.  They  can  be  stained  with  difficulty 
by  the  use  of  acid  dyes  only,  but  stain  best  when  both  an  acid  and  a 
basic  dye  are  used  either  in  mixture  or  sequence.  Perhaps  the  best 
dyes  for  the  purpose  are  Jenner's  and  Ehrlich's  triple  stain.  The  former 
method  and  iron-hEeniatoxylin  show  that  the  granules  are  situated  on 
the  nodal  points  of  the  reticulum  (Plate  III.,  11-14). 

2.  Eosinophil  Leucocytes. — The  eosinophils  are  readily  recognised  even 
in  unstained  specimens  by  the  large  size  and  high  refractile  index  of  the 
granules  in  their  protoplasm,  but  they  cannot  be  distinguished  from  the 
next  group  until  their  staining  reactions  have  been  ascertained.  The 
nucleus  has  the  same  general  characters  as  that  of  the  polymorpho- 

65  5 


66  THE  LEUCOCYTES 

nuclear  neutrophil  but  is  not  so  convoluted  as  the  former  frequently  is, 
and  trilobed  and  spectacle-shaped  forms  are  particularly  common.  The 
different  parts  seem  more  vesicular  and  to  possess  less  chromatin  than 
the  neutrophils.  The  protoplasm  is  packed  with  large  rounded  granules 
which  stain  deeply  with  acid  dyes.  When  basic  dyes  are  used  the 
granules  stand  out  clear  and  unstained  (Plate  III.,  15,  16). 

The  eosinophils  present  such  a  striking  picture  that  there  should  never 
h>e  any  doubt  about  their  identity.  In  certain  septic  and  parasitic  conditions 
neutrophil  granules  stain  with  special  brilliancy.  This  need  not  lead  to  con- 
fusion between  cells  with  neutrophil  and  eosinophil  granulation.  If  there  be 
reasonable  room  for  doubt  about  the  nature  of  a  granular  cell  it  is  safe  to 
conclude  that  it  is  not  an  eosinophil. 

3.  Basophil  Leucocytes  —  Mast-Cells.  —  Basophil  leucoytes  closely 
resemble  the  eosinophils  in  their  general  characters.  The  nucleus  is 
poorer  in  chromatin  and  the  trilobular  is  the  commonest  form.  The 
protoplasm  contains  a  variable  number  of  granules  which  stain  with 
basic  dyes  only.  They  are  loosely  arranged,  and  often  vary  greatly  in 
size  in  the  same  cell.  They  have  a  special  affinity  for  methylene  azur, 
so  that  with  methylene  blue  mixtures,  especially  in  alkaline  solution, 
they  stain  metachromatically  with  a  red-purple  tint.  In  certain  cases 
of  myelocythsemia  in  which  eosinophils  and  basophils  are  abundant 
very  striking  microscopic  pictures  may  be  obtained  with  such  a  stain  as 
Leishman's,  the  eosinophils  appearing  scarlet,  the  basophils  a  bright 
crimson.  Basophil  granules  are  not  stained  with  Ehrlich's  triple  stain 
or  with  eosine  and  hsematein  (Plate  III.,  17,  18). 

4.  Small  Lymphocytes. — These  cells  are  rather  smaller  than  the  ery- 
throcytes. The  nucleus  is  round  or  slightly  indented.  It  stains  deeply 
with  basic  dyes,  and  contains  irregularly  distributed  masses  of  chromatin 
of  varying  size.  The  protoplasm  is  relatively  scanty  and  often  appears  as 
a  mere  rim  round  the  nucleus.  It  stains  with  all  dyes — acid,  basic,  or 
neutral — but  has  a  special  affinity  for  basic  dyes,  and  particularly  for 
methylene  blue.  With  the  latter  dye  the  protoplasm  stains  darker  than 
the  nucleus,  and  appears  to  consist  of  a  light  blue  ground  substance 
in  which  is  embedded  a  reticulum,  the  nodal  points  of  which  are  very 
fine  basophil  granules.  These  granules  are  considerably  smaller  than 
those  of  the  first  three  varieties. 

Larger  azurophil  granules  can  be  demonstrated  in  varying  numbers 
in  a  large  proportion  of  the  small  lymphocytes.  These  granules,  as  well  as 
those  of  the  granular  series  proper,  are  probably  also  situated  on  nodal 
points  of  the  reticulum,  but  it  is  a  little  difficult  to  determine  this  point, 
as  stains  which  demonstrate  the  azur  granules  do  not  give  satisfactory 


THE   LEUCOCYTES  67 

pictures  of  the  reticulum.  The  longer  a  specimen  is  stained  with 
Irishman's  dye  the  greater  is  the  number  of  azurophil  granules  shown 
(Plate  III.,  3,  4). 

5.  Large  Lymphocytes. — Large  lymphocytes  have  the  same  general 
characters  as  the  small  lymphocytes.  There  are  transitions  between 
them,  and  it  is  frequently  a  matter  of  difficulty  to  classify  some  of  the 
intermediate  sizes.  The  large  lymphocytes  may  attain  a  diametric 
measurement  of  20  /*.  The  nucleus  is  generally  central,  rounded  or 
indented,  and  contains  a  less  proportion  of  chromatin  than  that  of  the 
small  lymphocytes.  The  protoplasm  is  relatively  more  abundant  than 
in  the  case  of  the  small  lymphocytes,  and  does  not  stain  so  deeply.  In 
addition  to  the  small  basophil  granules  there  are  frequently  azurophil 
granules  in  the  protoplasm  (Plate  III.,  5,  6). 

Large  Mononuclear  Leucocytes — Transitional  Leucocytes. — These  are 
varieties  of  leucocytes  which  are  frequently  classified  separately,  but 
which  seem  to  be  merely  special  types  of  the  large  lymphocyte.  The 
large  mononuclear  leucocytes,  large  hyaline  leucocytes  or  splenocytes, 
comprise  the  largest  individual  cells  of  the  lymphocyte  group.  The 
nucleus  is  generally  eccentric,  and  is  small  compared  to  the  amount 
of  protoplasm.  The  protoplasm  is  abundant,  shows  a  fairly  wide 
separation  of  the  meshes  of  the  reticulum,  and  consequently  does 
not  stain  deeply.  Azurophil  granules  are  present  in  varying  small 
numbers  (Plate  III.,  7,  8). 

The  transitional  leucocytes  are  very  similar  to  the  foregoing  variety 
except  in  the  relatively  smaller  amount  of  protoplasm  and  in  the  shape 
of  the  nucleus.  The  nucleus  is  considerably  indented,  and  may  be  horse- 
shoe-shaped or  twisted  (Plate  III.,  9,  10). 

The  name  "  transitional "  is  an  unfortunate  one.  It  has  no  merit  as  a 
descriptive  term,  and  is  misleading  in  so  far  as  it  suggests  that  the  cell  is  an 
intermediate  or  transitional  type.  The  relationship  between  the  mononuclear 
cells  is  discussed  in  Chap.  XIII. 

Leucocytes  not  found  in  Normal  Cieculating  Blood 

1.  Myelocytes. — Myelocytes  are  found  in  large  numbers  in  the  bone- 
marrow,  and  in  pathological  conditions  may  make  their  appearance  in 
the  blood-stream.  They  are  the  immediate  ancestors  or  immature  forms 
of  the  granular  leucocytes  of  the  circulation.     There  are  three  varieties — 

(a)  Neutrophil  Myelocytes. — These  show  variations  in  size  like  the 
corresponding  polymorphonuclear  neutrophils,  but  within  wider  limits. 
The  protoplasm  has  a  similar  slight  affinity  for  acid  dyes,  but  contains 


68  THE   LEUCOCYTES 

numerous  neutrophil  granules,  which  do  not  stain  so  well  as  the  poly- 
morph granules.  The  nucleus  is  relatively  large,  and  is  either  round  or 
indented.     It  does  not  stain  deeply  (Plate  III.,  26). 

(b)  Eosinophil  Myelocytes. — These  cells  have  the  same  relationship  to 
the  eosinophil  leucocytes  as  the  neutrophil  myelocytes  have  to  neutrophil 
polymorphs  (Plate  III.,  27). 

(c)  Basophil  Myelocytes. — Basophil  myelocytes  are  the  precursors  of 
the  basophil  leucocytes.  In  this  form  the  nucleus  is  frequently  very 
small.  The  protoplasmic  granules  are  much  more  tightly  packed  than 
in  the  basophil  polymorphs. 

Transitions  are  found  between  the  myelocyte  and  the  polymorphic 
in  all  three  types.  The  nucleus  becomes  more  and  more  indented,  then 
becomes  horseshoe-shaped.  Fresh  constructions  form,  and  the  lobulated 
condition  is  finally  attained. 

2.  Primitive  Forms. — (a)  In  conditions  where  myelocytes  are 
numerous  in  the  circulating  blood  a  certain  number  of  cells  are  found 
which  present  the  general  characters  of  myelocytes  but  with  basophil 
protoplasm  in  which  scanty  neutrophil  granules  are  embedded.  Those 
are  known  as  pro-myelocytes  (Plate  III.,  25). 

(&)  Under  certain  circumstances  large  mononuclear  basophil  cells 
which  differ  in  some  respects  from  ordinary  large  lymphocytes  may 
occur  in  the  circulation.  These  cells  were  described  by  Naegeli  as 
myeloblasts.  The  protoplasm  is  intensely  basophil,  and  usually  more 
abundant  than  in  typical  large  lymphocytes.  The  nucleus  has  its 
chromatin  arranged  in  a  fine  regular  network,  and  possesses  three  or 
four  nucleoli,  while  the  typical  large  lymphocyte  has  its  chromatin 
arranged  in  coarse  irregular  bands  and  has  never  more  than  two 
nucleoli  (Plate  III.,  24). 

(c)  It  may  be  that  in  certain  cases  a  cell  of  an  even  more  primitive 
type — the  undifferentiated  primitive  leucocyte — may  be  present. 

Plasma  Cells.1 — These  cells  exist  in  small  numbers  in  the  connective 
tissues  and  in  the  bone-marrow,  spleen,  and  lymph  glands.  They 
accumulate  in  great  numbers  in  the  granulomata,  especially  in 
syphilitic  lesions.  They  are  cells  of  lymphocyte  type  which  have 
undergone  modification  in  their  sojourn  through  many  generations  in 
an  extra-vascular  locus. 

The  cells  are  often  triangular  in  outline  and  the  nucleus  is  often 
tucked  away  at  one  corner,  so  that  the  cytoplasm  is  conspicuous.     The 
protoplasm  is  intensely  basophil  and  granular  in  character.     They  are 
1  For  discussion  and  references,  see  Downey,  Folia  Hcematologica,  xi.  i.  275. 


THE   LEUCOCYTES  69 

best  demonstrated  by  means  of  Pappenheim's  stain  after  fixation  in 
corrosive  sublimate.  One  per  cent,  solutions  of  resorcin,  pyronin,  and 
methyl  green  are  mixed  just  before  use  in  the  proportions  of  pyronin 
5  parts,  resorcin  10  parts,  and  methyl  green  15  parts.  The  staining 
should  be  controlled  by  observation  under  the  low  power,  and  slight 
variations  in  temperature  seem  to  affect  the  result.  In  successful 
preparations  the  cytoplasm  shows  a  bright  pyronin  red,  the  nucleus  a 
slate  green  with  bright  nucleoli.  Beside  the  nucleus  is  a  conspicuous 
centrosome. 

Plasma  cells  occur  in  the  circulation  in  some  cases  of  infantile 
aneemia  with  jaundice,  multiple  myeloma,  and  leucocytheemia. 

Pappenheim  identifies  plasma  cells  in  the  blood  with  the  peculiar  baso- 
phil cells  described  by  Turk  as  "  stimulation  forms  "  (Eeizungsformen). 

Leucocyte  Granules. — Fine  granules  can  be  brought  out  in  some  of 
the  leucocytes  by  staining  with  fuchsin.  These  are  known  as  Schriclde's 
granules.  At  one  time  they  were  thought  to  exist  only  in  lymphocytes, 
but  there  is  no  doubt  that  they  also  exist  in  the  myeloblasts.  Azuro- 
phil granules  exist  in  the  myeloblasts  as  well  as  in  the  differentiated 
lymphocytes.  They  do  not  ripen  to  become  neutrophil  granules  but 
disappear,  while  the  neutrophil  granules  arise  in  the  protoplasm  inde- 
pendently. In  young  eosinophils  some  of  the  granules  may  stain  blue 
with  eosine-methylene  blue  dyes.  These  may  be  looked  upon  as  young 
or  unripe  eosinophil  granules,  but  it  should  be  noted  that  they  are 
basophil,  not  azurophil. 

Differential  Counting  of  Leucocytes. — It  is  frequently  a  matter  of 
great  diagnostic  importance  to  make  a  differential  count.  The  principle 
is  easy,  the  practice  laborious.  The  requisites  are  an  evenly  spread  and 
stained  blood  film,  a  microscope  with  an  oil-immersion  lens,  and  a  paper 
and  pencil.  The  use  of  a  mechanical  stage  greatly  facilitates  the  count 
and  increases  its  accuracy,  and  Ehrlich's  square  eye-piece,  the  aperture 
of  which  can  be  altered,  is  sometimes  an  advantage. 

A  series  of  columns  is  headed  with  the  names  of  all  the  varieties  of 
leucocytes  likely  to  be  met  with,  and  it  is  convenient  to  reserve  two 
columns  to  record  the  incidence  of  megaloblasts  and  normoblasts. 

Beginning  at  (say)  the  top  left-hand  corner  of  the  film  as  it  appears 
under  the  microscope,  one  examines  the  whole  top  edge  of  the  film 
passing  from  left  to  right.  The  field  immediately  below  is  then  brought 
into  view,  and  the  corresponding  breadth  of  film  is  examined  passing 
from  left  to  right. 


70 


THE   LEUCOCYTES 


Each  and  every  leucocyte  (or  nucleated  red  cell)  that  is  seen  is  noted 
in  the  appropriate  column.  When  the  total  number  counted  has  reached 
300  the  sum  of  each  variety  is  divided  by  3,  and  this  represents  the 
percentage. 

It  is  often  stated  that  at  least  500  or  even  1 000  leucocytes  should  be 
counted  in  order  to  give  satisfactory  percentages.  While  granting  that  in 
theory  the  greater  number  counted  should  lead  to  greater  accuracy,  we  think 
it  rarely  necessary  to  count  more  than  300.  We  have  repeatedly  been  struck 
by  the  close  agreement  of  differential  counts  made  in  large  classes  by  com- 
parative novices  when  small  total  numbers  had  been  counted. 

Normal  Proportions  of  Leucocytes. — The  proportions  of  leucocytes 
which  are  found  in  healthy  blood  vary  somewhat.  The  following  limits 
are  physiological : — 


Polymorphonuclear  leucocytes 

60  to  75 

per  cent. 

Small  lymphocytes  . 

15  to  30 

>? 

Large  lymphocytes  (transitionals,  etc) 

.      3  to  10 

;> 

Eosinophil  leucocytes 

0-5  to  4 

)> 

Basophil  leucocytes 

0-025  to  1 

») 

A  shorter  and  convenient  statement  is — 

Polymorphs 

70  per  cent 

rrage- 

Small  lymphocytes  . 

20       „ 

Large  lymphocytes  . 

5        „ 

Eosinophils  .... 
Basophils     .... 

4        „ 
1        „ 

[maximum 

Functions  of  Leucocytes. — Studied  on  the  warm  stage  the  leucocytes 
are  found  to  be  capable  of  amoeboid  movement  though  in  different  degree. 
The  power  of  amoeboid  movement  may  be  regarded  as  proportionate  to 
the  degree  of  complexity  of  nuclear  structure.  Thus  the  most  active  cells 
are  the  polymorphonuclear  neutrophils.  The  other  granular  polymorphs 
come  next.  The  cells  of  the  lymphocyte  series  show  amoeboid  move- 
ments to  a  less  extent,  and  within  the  series  the  power  of  movement 
varies  with  the  relationship  of  protoplasm  to  nucleus.  The  nucleus  may 
be  regarded  as  a  hindrance  to  amoeboid  movement.  The  transitional 
cells  with  their  horseshoe  nucleus  are  thus  more  active  than  the  large 
lymphocytes,  and  the  large  lymphocytes  with  their  relatively  abundant 
protoplasm  are  more  active  than  the  small  lymphocytes.  Even  the 
myelocytes,  which  appear  in  the  peripheral  blood  only  in  pathological 
conditions,  are  capable  of  a  slight  amount  of  amoeboid  movement. 

The  leucocytes  are  also  capable  of  ingesting  micro-organisms,  their 


THE   LEUCOCYTES  71 

power  in  this  direction  depending  upon  their  amoeboid  activity  and 
amount  of  protoplasm.  Very  large  numbers  of  organisms  may  be  taken 
up  by  the  polymorph  neutrophils  on  account  of  their  activity,  and  by  the 
large  lymphocytes  on  account  of  their  size. 

Protection. — Their  capability  of  amoeboid  movement  and  of  phago- 
cytosis, and  the  fact  that  the  number  of  leucocytes  in  the  circulating  blood 
is  increased  in  the  blood  in  most  cases  of  infectious  disease,  indicate 
that  they  play  an  important  part  in  the  protection  of  the  body  against 
bacterial  and  toxic  diseases.  The  phagocytic  index — the  average  number 
of  micro-organisms  taken  up  by  the  leucocytes  of  a  person  suffering  from 
a  bacterial  infection  as  compared  with  the  average  number  taken  up  by 
>  the  leucocytes  of  a  healthy  person  under  similar  conditions — is  often 
ascertained  as  a  means  of  estimating  prognosis  or  the  effect  of  treatment. 
The  neutrophils  are  found  only  in  warm-blooded  animals.  Muir  has 
pointed  out  that  this  is  due  to  the  fact  that  organisms  develop  much 
more  rapidly  in  the  tissues  of  warm-blooded  animals  than  they  do  in  the 
tissues  of  cold-blooded  animals,  and  that  therefore  this  special  class  of 
cells  has  been  differentiated  to  defend  the  body  against  them,  and  that 
the  phenomenon  of  leucocytosis  in  warm-blooded  animals  and  the 
exceeding  rapidity  of  its  occurrence  has  to  do  with  their  urgent  need 
of  protection.  Neutrophil  cells  are  not  found  in  the  tissues  under 
normal  conditions.  They  appear  there  only  in  response  to  chemiotactic 
stimuli,  and  either  perish  there  or  return  to  the  blood  when  the  need 
for  them,  is  past. 

The  eosinophils  seem  to  have  a  special  relation  to  the  toxins  of  para- 
sites such  as  filaria,  and  possibly  also  to  metabolic  poisons  such  as  those 
concerned  in  the  production  of  asthma  and  some  skin  affections. 

The  lymphocytes  also  increase  in  the  peripheral  blood  in  response  to 
invasion  by  a  very  limited  number  of  special  toxins,  such  as  those  of 
whooping-cough  and  syphilis.  The  collections  of  lymphocytes  round 
the  respiratory  and  alimentary  tracts  may  have  to  do  with  the  fact  that 
these  situations  are  inhabited  normally  by  attenuated  and  non- virulent 
organisms,  and  that  possibly  the  lymphocytes  are  adapted  and  sufficient 
to  keep  them  in  check,-  and  their  relatively  small  percentage  in  the  blood 
is  due  to  the  fact  that  they  multiply  so  easily  in  connective  tissue  that 
the  blood  protection  can  easily  be  reinforced  from  that  source. 

It  has  been  suggested  that  neutrophils  break  down  to  form  anti- 
toxins, but  of  this  there  is  no  definite  proof. 

Absorption  and  Assimilation  of  Food. — An  increase  in  the  number 
of  leucocytes  in  the  circulating  blood  takes  place  during  digestion,  and 


72  THE   LEUCOCYTES 

it  has  been  suggested  that  they  play  a  part  in  the  absorption,  transport, 
and  assimilation  of  protein,  fat,  carbohydrate,  and  iron. 

Glycogen  is  easily  demonstrated  in  many  of  the  neutrophils  in  certain 
inflammatory  conditions,  but  its  significance  is  not  definitely  known.  It 
is  probably  not  a  degenerative  change,  and  appears  more  likely  to  be 
associated  with  protection.  The  glycogen  seems  to  be  taken  up  in  the 
blood  and  carried  to  the  point  which  is  threatened  by  organisms,  and 
possibly  may  there  serve  to  nourish  fibroblasts  and  other  young  cells. 

It  has  been  suggested  that  the  leucocytes  play  a  part  in  maintaining 
the  constancy  of  the  protein  content  of  the  blood  plasma.  In  this 
connection  they  might  be  regarded  as  secreting  glands. 

Ferments. — The  leucocytes  give  rise  to  proteolytic  and  diastatic 
ferments,  to  oxydase,  to  pro-thrombin  and  thrombokinase. 

The  proteolytic  ferment  is  not  present  in  the  small  lymphocytes. 

The  proteolytic  ferment  of  the  neutrophils  is  capable  of  acting  in 
neutral,  alkaline,  or  acid  media.  The  cells  in  myelocythsemia  act  best 
in  alkaline  media.1 

The  oxydase  and  blood-clotting  agents  are  discussed  elsewhere. 
1  See  Longcope  and  Donhauser,  Journ.  of  Exper.  Med.,  x.  1908,  618. 


CHAPTER  VIII 

VARIATIONS   IN  THE   NUMBER  AND   PROPORTIONS   OF 

LEUCOCYTES 

Diminution  of  Leucocytes,  Leucopenia 

I.  Physiological. — Diminution  in  the  number  of  leucocytes  only  occurs 
to  a  very  slight  extent  in  physiological  conditions.  In  certain  indi- 
viduals the  leucocyte  count  is  always  low.  The  prolonged  application 
of  cold  or  the  effect  of  baths,  either  hot  or  cold,  may  diminish  their 
number. 

II.  Pathological. — 1.  In  starvation  and  malnutrition  of  non-toxic 
origin  the  numbers  fall. 

2.  In  a  few  of  the  acute  infections  there  may  be  considerable 
leucopenia.  This  is  notable  in  typhoid  fever.  In  measles,  Malta 
fever,  influenza,  and  tuberculosis  it  is  usual  but  not  so  constant. 
Injections  of  serum  may  cause  leucopenia. 

3.  In  infections  by  animal  parasites,  malaria,  kala-azar,  and  try- 
panosomiasis there  is  usually  leucopenia. 

4.  In  some  of  the  blood  diseases  low  counts  are  found.  In  pernicious 
anaemia  the  number  per  cubic  millimetre  rarely  exceeds  5000.  In 
splenic  anaemia  the  numbers  are  still  smaller.  Rarely  in  leucocythaemia 
during  a  remission  or  in  the  course  of  a  complication  such  as  pneumonia 
the  leucocyte  count  may  reach  a  very  low  figure. 

5.  In  severe  toxaemias  when  reaction  is  overwhelmed  there  may  be 
leucopenia. 

6.  A  transient  leucopenia  often  occurs  in  traumatic  conditions  and 
shock. 

In  the  above  conditions  the  diminution  mainly  affects  the  poly- 
morphonuclear cells.  Diminution  of  eosinophils  occurs  in  most 
fevers,  in  malignant  disease  with  some  notable  exceptions,  and  after 
haemorrhage. 

Increase  of  Leucocytes,  Leucocytosis 

I.  Physiological. — High  leucocyte  counts  are  physiological  under 
certain  circumstances. 

73 


74        NUMBER   AND   PROPORTIONS   OP   LEUCOCYTES 

1.  Infancy. — The  average  leucocyte  count  in  infants  during  the 
first  four  days  is  about  18,000.  The  number  soon  falls,  and  by  the 
tenth  day  is  about  14,000,  by  the  twelfth  month  10,000.  The  per- 
centage of  polymorphs  during  the  first  four  days  is  about  66.  The 
polymorph  percentage  then  falls,  being  about  55  by  the  tenth  day, 
and  as  low  as  30  about  the  end  of  the  first  year.  Between  the  ages 
of  1  and  12  years  the  polymorph  percentage  is  about  50 ;  after  12 
it  soon  approximates  to  the  adult  figure.  The  number  of  lymphocytes 
varies  correspondingly,  the  number  of  eosinophils  remaining  fairly 
constant  and  similar  to  the  adult  proportions. 

2.  Pregnancy. — In  many  instances  pregnancy  is  associated  with  an 
increase  in  the  number  of  white  cells. 

3.  Digestion. — An  hour  after  taking  food  the  number  of  leucocytes 
begins  to  rise,  reaches  its  maximum  in  about  four  hours,  and  has  fallen 
to  the  normal  in  about  six  hours.1  The  degree  of  leucocytosis  is  greater 
if  food  has  been  previously  withheld  for  at  least  twelve  hours.  In 
ordinary  circumstances  digestion  leucocytosis  is  but  slight  (an  increase 
of  1000-1500  per  c.mm.),  as  food  is  taken  at  intervals  much  shorter  than 
the  time  occupied  by  the  rise  and  fall  which  take  place  after  a  single 
meal.  In  other  words,  digestion  leucocytosis  in  varying  intensity  is 
usually  a  chronic  condition  in  well-nourished  people. 

The  cells  which  participate  most  constantly  are  the  lymphocytes, 
but  the  polymorphs  may  increase  to  a  much  greater  degree.  Eosino- 
phils show  very  little  change,  but  are  usually  slightly  increased.  The 
source  of  the  leucocytes  constituting  digestion  leucocytosis  is  the 
bone-marrow.2  Protein  food  causes  a  greater  leucocytosis  than  fat  or 
carbohydrate. 

Young  subjects  have  a  greater  leucocyte  increase  after  food  than 
adults.  It  has  been  found  that  digestion  leucocytosis  does  not  occur 
in  cases  of  gastric  cancer,  and  in  some  other  conditions  such  as  gastric 
inertia.  During  pathological  leucocytosis  digestion  may  cause  a 
diminution  in  the  numbers  in  the  peripheral  blood. 

4.  Leucocytosis  of  the  Moribund — Terminal  Leucocytosis. — A  consider- 
able rise  in  the  leucocyte  count  may  occur  shortly  before  death.  This 
does  not  occur  when  death  occurs  suddenly,  but  when  the  moribund 
condition  is  prolonged  the  rise  in  numbers  may  be  considerable,  and 
is  probably  due  to  terminal  infections.  As  a  rule  the  increase  affects 
the  polymorphonuclear  cells.     In  pathological  conditions  there  may  be 

1  See  Goodall,  Gulland,  and  Pa  ton,  Journ.  of  Physiology,  1903,  1. 

2  Goodall  and  Paton,  Journ.  of  Physiology,  1905,  20. 


NUMBEE   AND   PEOPOETIONS   OF   LEUCOCYTES        75 

an  exaggeration  of  the  blood  picture  of  the  disease  in  question.  In 
pernicious  anaemia  there  may  be  a  very  striking  terminal  lymphocytosis, 
but  this  is  rare. 

5.  A  slight  increase  in  the  number  of  leucocytes,  chiefly  polymorpho- 
nuclears, may  occur  in  a  variety  of  conditions,  some  of  which  may  be 
mentioned  here.  These  are  profuse  perspiration,  stasis,  and  emotional 
conditions,  the  latter  in  so  far  as  they  may  affect  the  vasomotor 
system.  The  short  application  of  cold  or  cold  baths  may  cause  slight 
leucocytosis. 

Exercise  and  electric  stimulation  may  be  followed  by  a  rise  in  the 
leucocyte  count,  and  a  slight  leucocytosis  may  be  determined  by  the 
application  of  a  blister. 

II.  Pathological. — In  the  course  of  many  diseases  there  may  be 
considerable  increase  in  the  number  of  white  cells  in  the  blood.  In 
practically  all  cases  the  increase  is  brought  about  mainly  by  one  variety, 
so  that  there  is  marked  alteration  in  the  normal  proportions.  It  is 
therefore  convenient  to  classify  the  pathological  leucocytoses  according 
to  the  type  of  cell  chiefly  involved. 

I.  Neutrophil  Leucocytosis. — In  most  cases  the  number*  of  cells  per 
cubic  millimetre  is  not  very  greatly  raised.  The  lower  range,  from  10,000 
to  12,000,  is  a  much  commoner  finding  than  the  higher  counts  of  20,000 
to  30,000.  Simple  leucocytoses  of  100,000  have  been  noted,  but  are 
very  rare.  Bunting1  records  a  count  of  214,000  with  82*2  per  cent,  of 
polymorphs  in  a  case  of  empyema.  The  blood  picture  is  commonly  not 
greatly  altered,  the  mere  presence  of  an  increased  number  and  con- 
sequently an  increased  percentage  of  polymorphonuclear  neutrophils 
representing  the  main  change.  Though  the  percentage  of  lymphocytes 
is  usually  low,  the  actual  number  in  the  cubic  millimetre  may  be  high 
(see  p.  78).  In  the  majority  of  cases  the  proportion  of  large  lympho- 
cytes is  considerably  increased  at  the  expense  of  the  small  lymphocytes. 
Eosinophils  and  basophils  are  often  absent  or  reduced  to  the  minimum, 
especially  in  septic  cases.  When,  however,  the  leucocytosis  is  very 
great  or  of  long  standing  a  considerable  number  of  myelocytes  and 
young  forms  make  their  appearance.  Films  not  infrequently  show  the 
presence  of  a  concurrent  secondary  ansemia. 

Causes. — Stated  in  brief,  a  neutrophil  leucocytosis  occurs  in  malignant 
disease,  in  septic  and  inflammatory  conditions,  in  most  fevers  and  many 
toxic  conditions,  and  after  heemorrhage. 

1  Brit.  Med.  Joum.,  18th  May  1907. 


76        NUMBEK   AND   PEOPOETIONS   OF  LEUCOCYTES 

1.  Malignant  Disease. — Leucocytosis  is  by  no  means  a  constant 
feature.  When  present  it  may  be  of  considerable  diagnostic  significance. 
Its  absence  means  nothing  (Chap.  XXXII.). 

2.  Septic  and  Inflammatory  Conditions. — Leucocytosis  is  the  rule  in 
these  conditions.  Its  degree  varies  very  greatly,  and  seems  to  depend 
upon  the  nature  of  the  organism,  the  severity  of  the  infection,  and  the 
resistance  of  the  individual. 

3.  Fevers  and  Toxic  Conditions. — As  a  polymorphonuclear  leuco- 
cytosis is  the  rule  in  fevers,  it  is  unnecessary  to  give  a  list  of  the  con- 
ditions in  which  it  occurs.  It  is  important  to  note,  however,  that  there 
are  certain  exceptions.  These  are  typhoid,  influenza  (uncomplicated), 
measles  and  rotheln,  mumps,  malaria,  and  Malta  fever. 

Tubercular  conditions  are  not  usually  associated  with  a  polymorph 
leucocytosis,  but  it  usually  occurs  in  tuberculous  meningitis.  Smallpox 
and  whooping-cough  are  also  exceptions,  as  they  give  rise  to  lympho- 
cytosis. 

The  toxic  conditions  (not  specially  associated  with  inflammation) 
which  may  bring  about  a  polymorph  leucocytosis  are  very  numerous. 
Some  of  these  may  be  grouped  as  follows : — 

(a)  Eickets  and  gout,  acute  yellow  atrophy,  and  cirrhosis  of  the  liver. 

(&)  Poisoning  by  coal-gas,  the  salicylates  or  quinine,  and  the  action 
of  hsemolytic  agents  such  as  phenyl-hyclrazin. 

(c)  Injection  of  antitoxic  serum,  organic  extracts,  nuclein,  cinnamate 
of  soda,  etc. 

(d)  Injection  of  irritants  such  as  turpentine,  tallianine,  croton  oil, 
and  copper  sulphate. 

(e)  Ether  anaesthesia,  and  rarely  after  chloroform  anaesthesia. 

4.  Post- Hemorrhagic  Leucocytosis. — Soon  after  haemorrhage,  sometimes 
within  an  hour,  there  is  an  increase  of  polymorphonuclear  cells  in  the 
blood.  After  a  single  haemorrhage  the  leucocytosis  usually  disappears  in 
three  or  four  days. 

In  1904  Arneth1  made  a  division  of  the  polymorphs  into  five  classes 
according  to  the  number  of  segments  in  the  nucleus.  In  the  first  class  he 
placed  myelocytes  and  neutrophils  with  indented  or  horseshoe-shaped  nuclei ; 
in  the  second  class,  neutrophils  with  bilobed  nuclei ;  in  the  third  class,  tri- 
lobed ;  fourth  class,  four-lobed ;  fifth  class,  five-lobed,  or  still  further  seg- 
mented nuclei.  Each  rounded  lobule  or  loop  is  counted  as  a  segment.  A 
similar  classification  has  since  been  applied  to  the  eosinophils.2 

1  Arneth,  Die  neiitrophilen  toeissen  Bluikorperchen  bei  Infektionshranhheiien,  Jena, 
G.  Fischer,  1904.     (See  Folia  Hcematologica,  i.  492  et  seq.;  also  vii.  83.) 

2  Arneth,  Deutsche  Archivf.  klin.  Med.,  xcix. 


NUMBEE  AND   PEOPOETIONS   OF  LEUCOCYTES        77 

In  normal  conditions  Arneth  states  the  proportions  to  be  as  follows  : — 

Class  I.  II.  III.  IV.  V. 

Neutrophils        .5  35  41  17  2  per  cent. 

Eosinophils        .11  69  19  1  „  ;■    ' 

In  toxic  conditions  he  considers  that  the  older  cells  are  killed  off  more 
readily,  so  that  there  are  fewer  cells  in  classes  IV.  and  V.,  hence  the  blood- 
picture  is  dislocated  to  the  left. 

These  views  have  been  subjected  to  much  criticism.  There  is  no  general 
agreement  that  the  cells  of  classes  IV.  and  V.  are  necessarily  older  than  those 
of  classes  II.  and  III.,  and  some  authors  hold  that  certain  of  the  cells  with 
rounded  nuclei  in  Arneth's  class  I.  are  not  young  cells  but  degenerated  forms. 
In  spite  of  doubt  about  the  significance  of  the  results  there  is  a  considerable 
consensus  of  opinion  in  favour  of  the  practical  utility  of  the  method.  Many 
suggestions  have  been  offered  with  the  object  of  facilitating  the  procedure 
and  of  obtaining  a  simple  expression  of  the  results. 

Schilling-Torgau x  classifies  the  neutrophils  as  follows  : —  Myelocytes, 
myelocytes  with  notched  nuclei,  cells  with  rod-shaped  nuclei,  cells  with 
segmented  nuclei.  This  classification  is  much  more  easily  carried  out,  and  is 
said  to  convey  the  same  information  as  a  more  extended  Arneth  count. 

Pappenheim  holds  that  it  is  sufficient  to  state  the  number  of  nuclear 
segments  in  100  leucocytes.  Another  suggestion  is  that  the  sum  of  the 
percentages  in  classes  I.  and  II.  and  half  the  percentage  of  class  III.  should 
be  stated  as  the  nuclear  index. 

It  has  been  claimed  that  in  fevers  and  inflammatory  conditions  Arneth's 
method  is  a  guide  to  diagnosis  and  prognosis,  and  that  in  pre-existing  illness 
it  may  give  the  first  indication  of  an  inflammatory  complication.  It  has  its 
warmest  advocates  among  those  who  have  utilised  it  as  a  guide  in  the 
administration  of  serums  and  the  estimation  of  prognosis  in  cases  of  tuber- 
culosis. There  is  no  doubt  that  in  cases  with  leucocytosis  the  presence  of  a 
moderately  high  percentage  of  neutrophils  with  rounded,  kidney-shaped,  or 
horseshoe-shaped  nuclei  indicates  a  severe  infection.  The  observer  very  soon 
learns  to  recognise  that  an  unusual  number  of  these  cells  is  present  without 
making  a  special  differential  count  of  the  neutrophils. 

II.  Lymphocytosis. — The  term  lymphocytosis  is  applied  to  two  groups 
of  conditions — (1)  Where  there  is  no  increase  in  the  number  of  white 
cells  per  cubic  millimetre,  but  where  there  is  a  high  percentage  of 
lymphocytes  and  a  correspondingly  low  percentage  of  polymorphs 
(relative  lymphocytosis).  (2)  Where  there  is  increase  in  the  number 
of  white  cells  per  cubic  millimetre  as  well  as  a  high  percentage  of 
lymphocytes  (absolute  lymphocytosis). 

The  term  "  relative  lymphocytosis "  is   conventionally  applied   to   the 

1  Schilling-Torgau,  Folia  Hcematologica,  xii.  1  Teil,  1911,  130  (full  references  to 
literature). 


78        NUMBER  AND   PROPOPtTIONS   OF   LEUCOCYTES 

condition  stated  above,  but  only  a  consideration  of  the  actual  figures  will 
determine  whether  the  description  "  relative  lymphocytosis  "  or  "  leucopenia  " 
(diminution  of  polymorphs)  is  the  more  accurate.  Unfortunately  the  term 
"relative  lymphocytosis"  is  often  applied  to  conditions  in  which  there  is  a 
low  total  white  cell  count  with  a  high  lymphocyte  percentage  although  the 
actual  number  of  lymphocytes  per  cubic  millimetre  is  normal.  These  should 
be  described  as  "leucopenia." 

In  order  to  obtain  a  clear  idea  of  the  real  relations  between  the  different 
varieties,  it  is  often  advisable  to  calculate  out  the  actual  numbers  of  each 
kind  of  cell  in  the  cubic  millimetre  instead  of  expressing  them  by  percentages. 
Thus,  if  we  take  7000  as  the  normal  number  of  leucocytes,  and  use  the 
short  table  on  page  70  for  their  proportions,  we  should  get  the  following 
numbers  : — 


Polymorphs     . 
Small  lymphocytes 
Large  lymphocytes 
Eosinophils 
Basophils 


If  the  total  count  be  4000,  and  the  proportions  be 


Polymorphs 

Lymphocytes 

Eosinophils 


4900 

1400 

350 

280 

70 

7000 

49 

48 

3 


}l750 


the  beginner  is  apt  to  assume  that  the  lymphocytes  are  considerably 
increased.  When  the  sum  is  worked  out,  however,  and  the  total  numbers 
are  found  to  be 


Polymorphs  . 
Lymphocytes  . 
Eosinophils 


1960 

1920 

120 

4000 


it  is  seen  that  the  lymphocytes  are  well  within  the  normal  limit  of  variation, 
and  that  the  real  change  is  a  diminution  of  polymorphs.  On  the  other  hand, 
with  a  leucocytosis  of  20,000,  with  the  very  common  proportions  in  such  a 
case,  of  \ 

Polymorphs     .  .  .  .  .90 

Lymphocytes  .  .  .  .  .10 


the  total  numbers  would  be 

Polymorphs 
Lymphocytes  . 


18,000 
2,000 


so    that  the  lymphocytes  in  spite  of  their  low  percentage  are  about  the 
normal,  and  the  increase  is  due  to  the  polymorphs. 


NUMBEE  AND   PKOPOKTIONS   OF  LEUCOCYTES        79 

Although  for  convenience  we  continue  to  use  the  percentage  expression, 
the  necessity  for  this  calculation  is  always  understood. 

Eelative  lymphocytosis  occurs  in — 

(1)  Congenital  and  acquired  syphilis  in  the  secondary  stage,  and  in 
uncomplicated  tuberculosis. 

(2)  Pernicious  anseniia,  chlorosis,  scurvy,  hsemophilia.  (Leucopenia 
is  more  common  in  the  first  two  of  these.) 

(3)  Some  cases  of  goitre  and  exophthalmic  goitre. 

(4)  Some  cases  of  malaria,  typhoid,  measles,  and  mumps. 

(5)  Some  cases  of  chronic  catarrh  of  the  small  intestine. 
Absolute  lymphocytosis  is  the  chief  feature  of  the  blood  in — 

(1)  Lymphatic  leukaemia. 
It  also  occurs  in — 

(2)  Some  cases  of  tuberculosis  and  syphilis. 

(3)  Whooping-cough. 

(4)  Smallpox. 

(5)  It  has  been  induced  experimentally  by  injections  of  pilocarpin 
(Waldstein l),  iodine  (Bezancon  et  Labbe" 2),  and  lecithin,  in  rabbits  by 
dead  non-toxic  animal  matter  (Holmes  3),  and  in  frogs  by  injections  of 
bacterial  cultures  or  their  filtrates  (Proscher4). 

III.  Eosinophilic^ — Eosinophilia  is  said  to  exist  when  the  number  of 
eosinophil  leucocytes  in  the  blood  exceeds  4  per  cent. 
The  conditions  under  which  this  occurs  include — 

(a)  Myelocythsemia. 

(b)  Infection  by  various  animal  parasites. 

(c)  Certain  infectious  diseases. 

(d)  Certain  cases  of  asthma  during  the  paroxysms. 

(e)  Some  skin  diseases. 

(/)  Certain  toxic  and  experimental  conditions. 

(a)  Myelocytlicemia. — See  Chap.  XXI. 

(b)  Infection  by  Various  Animal  Parasites — (i.)  Intestinal  Parasites. 
— Eosinophilia  may  occur  in  the  course  of  infection  with  almost  any  of 
the  intestinal  parasites,  but  only  in  the  case  of  a  few  is  it  constant  and 
definite.  It  is  probable  that  the  factor  determining  the  eosinophilia  is 
irritation  of  the  intestine  (see  Chap.  XXXIII.). 

1  Berl.  klin.  Wochenschr.,  1895. 

2  Traite  d'He'matol.,  1904,  627. 

3  Guy's  Hospital  Reports,  lix.  155. 

4  Folia  Hcematologica,  i.  1904,  571. 


80        NUMBEE  AKD   PEOPOETIONS   OF  LEUCOCYTES 

(ii.)  Other  Animal  Parasites — Bilharzia  Hcematobia. — Eosinophilia  is 
the  rule.     Coles l  recorded  a  ease  showing  20  per  cent. 

Distomiasis. — Ward2  records  a  case  of  distoma  hepaticum  infection 
in  a  man  in  whom  the  percentage  of  eosinophils  reached  41/6. 

Filariasis. — As  first  recorded  by  Gulland,3  eosinophilia  is  the  rule. 
Four  to  10  per  cent,  is  common.  Eemlinger  4  found  70  per  cent,  in  cases 
with  chyluria.     A  slight  neutrophil  leucocytosis  may  also  be  present. 

Dracontiasis. — Balfour5  found  6  to  36  per  cent,  of  eosinophils  in 
six  cases  of  guinea-worm  infection. 

(c)  Eosinophilia  occurs  in  different  stages  of  such  conditions  as 
scarlet  fever,  pneumonia,  etc.,  and  will  be  discussed  in  connection  with 
these  conditions. 

(d)  Asthma. — An  increase  of  eosinophils  in  the  blood  and  sputum 
occurs  in  many  cases  of  bronchial  asthma,  especially  just  before  and 
during  the  paroxysms.  The  phenomenon  may  be  absent,  so  that 
a  negative  finding  has  no  diagnostic  significance.  The  presence  of 
eosinophilia  assists  in  distinguishing  between  true  asthma  and  dyspnoea 
from  other  causes. 

(e)  Skin  Diseases. — In  some  diseases  of  the  skin  there  may  be  con- 
siderable eosinophilia.  The  conditions  in  which  it  is  most  constant  are 
pemphigus  and  dermatitis  herpetiformis.  With  much  less  frequency 
eosinophilia  occurs  in  other  bullous  eruptions,  urticaria,  and  eczema. 

(f)  Toxic  and  Experimental  Conditions. — (i.)  Eosinophilia  has  been 
recorded  in  osteomalacia,  chronic  osteomyelitis,  rickets,  and  bone 
tumours. 

(ii.)  Phosphorus  poisoning  has  been  stated  to  cause  eosinophilia. 

(hi.)  Eosinophilia  has  been  caused  in  rabbits  by  intravenous  injec- 
tions of  extracts  of  tenia  saginata  in  salt  solution  (Proscher  and 
Pappenheim 6).     The  eosinophils  are  nearly  all  myelocytes. 

IV.  Basophilia. — Basophilia  occurs  in  the  following  conditions : — 

(a)  Myelocythsemia  (Chap.  XXL). 

(b)  Staphylococcus  Infections. — Some  degree  of  basophilia  may  occur 
in  the  human  subject.  It  has  been  produced  experimentally  in  rabbits 
by  injections  of  staphylococcus  toxin. 

1  Diseases  of  the  Blood,  1905. 

2  Brit.  Med.  Journ.,  i.  1911. 

3  Brit.  Med.  Journ.,  1902. 

4  Soc.  de  Biologie,  1902. 

5  Lancet,  1903. 

6  Folia  Haimatologica,  i.  638.  (An  account  of  other  experimental  leucocytoses  is 
given  here.) 


NUMBER  AND   PROPORTIONS   OF  LEUCOCYTES        81 

(c)  Injections  of  pyrodin,  hemialbumose,  colchicine,  and  phrynolysin 
have  been  found  to  cause  basophilia.  The  latter  brings  about  an  in- 
crease of  mononuclear  basophils  (Proscher  and  Pappenheim).  Similar 
results  have  followed  the  injection  of  milk  and  cancer  extracts. 

(d)  Occasional  instances  of  a  minor  degree  of  basophilia  are  not 
very  rare.  At  present,  however,  there  are  no  data  which  would  permit 
of  any  grouping  of  these  cases.  Dickson l  found  an  increase  up  to  2  per 
cent,  in  four  cases  of  acromegaly. 

1  Dickson,  The  Bone  Marrow,  Longmans. 


CHAPTER  IX 

THE  BLOOD-PLATES:    HiEMOCONIA 

Blood-Plates. — In  a  drop  of  fresh  blood  the  blood-plates  appear  as 
colourless,  refractile,  discoid  bodies,  varying  in  size  from  1  to  3 
micromillimetres  in  diameter. 

They  show  a  great  tendency  to  adhere  to  each  other  and  to  any 
foreign  body  with  which  they  may  come  into  contact.  This  leads  to 
considerable  difficulty  in  studying  their  morphology  and  in  estimating 
their  numbers.  In  films  stained  by  eosine-methylene  blue  combinations, 
such  as  Jenner's  stain,  they  show  an  affinity  for  basic  dyes.  Their  out- 
lines are  rather  indefinite  and  irregular,  and  in  the  centre  they  usually 
exhibit  an  area  of  chromatin  substance  staining  more  intensely  than 
the  periphery.  This  is  regarded  by  some  observers  as  a  nucleus.  It  is 
brought  out  much  better  by  such  Romanowsky  modifications  as  Leish- 
man's  and  "Wright's  stains,  with  which  the  central  bodies  stain  a  brilliant 
red,  like  the  nuclei  of  leucocytes. 

Opinions  vary  considerably  regarding  the  nature  of  the  blood-plates. 
The  chief  views  regarding  them  are  as  follows  : — 

1.  That  they  are  broken  pieces  of  white  cells  or  their  nuclei  (Max 
Schultze,  Riess). 

2.  That  they  are  nuclear  remains  derived  from'  red  corpuscles  by 
extrusion  (Engel,  Pappenheim,  Maximow,  Schwalbe,  Arnold).  That 
they  represent  the  normoblast  nucleus,  altered  by  a  process  of  physio- 
logical metamorphosis  as  described  on  page  57  (Schilling-Torgau). 

3.  That  they  are  nucleated  cells  which  constitute  a  third  type  of 
formed  element  of  the  blood  (Hayem,  Bizzozero,  Deetjen). 

Deetjen 1  studied  the  blood-plates  on  glass  slides  covered  with  a  film  of 
jelly  made  as  follows  : — 

5  grms.  agar  are  boiled  in  500  c.c.  distilled  water  for  half  an  hour. 
To  each  100  c.c.  of  filtrate  are  added — 
0#6  grm.  sodium  chloride. 
6 "8  c.c.  of  a  10  per  cent,  watery  solution  of  metaphosphate  of 

sodium  (Merck). 
5  c.c.  of  a  10  per  cent,  watery  solution  of  potassium  bisulphate. 

1  Deetjen,  Archivf.  Path.  Anal,  1898,  164. 

82 


THE   BLOOD-PLATES:   ELEMOCONIA  83 

His  observations  on  the  warm  stage  led  him  to  the  conclusion  that  the 
blood-plates  were  nucleated  cells  capable  of  amoeboid  movement. 

4.  That  they  form  an  independent  but  non-nueleated  element  of 
the  blood. 

5.  That  they  are  precipitates  from  the  plasma. 

The  vastly  greater  number  of  plates  which  appears  when  Deetjen's 
method  is  employed  suggests  the  view  that  a  proportion  of  the  plates 
at  least  are  precipitates.1 

6.  That  they  are  detached  portions  of  the  cytoplasm  of  the  giant 
cells  of  the  spleen  and  bone  marrow  (Wright,2  Bunting,3  Downey4). 

In  sections  stained  by  his  modification  of  Leishman's  method  Wright 
finds  that  the  blood-plates  show  a  light  blue  hyaline  periphery  and  a  central 
part  crowded  with  red  or  violet  granules.  He  finds  the  same  differentiation 
of  the  giant  cell  protoplasm,  and  notes  a  marked  tendency  of  the  giant  cells 
to  form  pseudopodia.  These  pseudopodia  may  project  into  vessels,  and  often 
show  constrictions  and  segmentation  into  bodies  which  resemble  the  blood- 
plates.  He  further  points  out  that  only  in  mammals  are  blood-plates  found, 
and  that  only  in  mammals  are  giant  cells  found. 

He  also  notes  a  parallelism  between  the  number  of  plates  and  giant  cells 
in  various  pathological  conditions. 

.  Many  authorities  admit  a  multiple  origin  of  the  blood-plates,  and 
some  make  a  distinction  between  plates  derived  from  red  cells  and 
plates  derived  from  white  cells. 

There  are  difficulties  in  the  way  of  accepting  any  of  the  views 
hitherto  propounded,  and  while  we  may  state  that  we  regard  the 
blood-platelets  as  derivatives  of  the  white  cells,  particularly  poly- 
morph nuclei,  we  offer  the  opinion  with  no  great  confidence.  We 
consider  that  these  plates  exist  in  the  blood  before  it  is  shed. 

The  so-called  blood-plates  which  increase  in  the  plasma  after  blood 
is  shed  are  to  be  regarded  as  precipitates. 

Number  of  Blood- Plates. — Very  diverse  statements  are  made  regard- 
ing the  number  of  blood-plates  in  health.  The  average  may  be  taken 
as  300,000  per  c.mm.5 

Variations  in  Pathological  Conditions — Diminution. — 1.  The  blood- 

1  Buckmaster,  Morphology  of  Normal  and  Pathological  Blood.     London,  1910. 

2  Wright,  Boston  Med.  and  Surg.  Journ.,  1906,  643. 

3  Bunting,  Journ.  Exp.  Med.,  xi.  451. 

4  Downey,  Folia  Hcemotologica,  xv.  Archiv,  1913,  p.  25. 

3  See  Pratt,  Journ.  Arner.  Med.  Assoc,  1905  ;  Tschistowitscli,  Folia  Hcematologica, 
1907,  295 ;  and  Aynaud,  These  de  Paris,  1909,  Steinheil,  for  discussion  and 
references  to  literature. 


84  THE   BLOOD-PLATES:   ILEMOCONIA 

plates  are  diminished  in  infectious  diseases  [with  the  exception  of 
scarlet  fever  (Tschistowitsch)]  during  the  febrile  stage.  They  are 
diminished  in  infection  by  animal  parasites.1  There  is  no  relationship 
between  the  number  of  blood-plates  and  leucocytes. 

2.  The  plates  are  diminished  in  haemophilia,  purpura,  and  leuco- 
cythaemia. 

3.  There  is  a  great  reduction  in  the  number  of  blood-plates  in 
pernicious  anaemia,  but  they  are  often  greatly  increased  in  size. 

4.  They  are  diminished  in  cachexia,  malnutrition,  and  in  some 
cases  of  cancer.  In  cancer  with  marked  secondary  anaemia  the  plates 
may  be  normal  or  increased. 

Increase. — 1.  There  is  a  marked  increase  of  blood-plates  after  even 
slight  haemorrhage. 

2.  They  are  increased  in  most  cases  of  chlorosis. 

3.  They  are  increased  in  most  inflammatory  and  septic  conditions. 

Hsemoconia.2 — Haemoconia  consist  of  small,  colourless,  highly  refrac- 
tile  bodies  which  are  found  in  normal  and  pathological  blood.  They 
are  usually  round,  but  may  be  rod-shaped  or  dumb-bell-shaped.  They 
vary  in  size  from  0'5  to  4  /*.  They  exhibit  Brownian  movement. 
They  do  not  stain  with  ordinary  methods,  nor  with  osmic  acid  or  sudan. 
The  nature  of  these  bodies  is  uncertain.  Some  of  them  are  doubtless 
extruded  leucocyte  granules  or  pieces  of  broken  cells.  Muhlmann 
considers  that  they  are  in  part,  at  least,  of  a  fatty  nature,  and  finds 
that  they  are  increased  in  the  blood  after  a  meal  rich  in  fat. 

1  Darling,  Trans.  Soc.  of  Trop.  Med.  and  Hygiene,  v.  1911. 

2  Miiller,  Centralb.  fur  allg.  Path.,  1896 ;  Stokes  and  Wegefarth,  Johns  Hopkins 
Hosp.  Bulletin,  1897  ;  Love,  Lancet,  1904  ;  Muhlmann,  Berl.  Hin.  Wochenschr.,  1907  ; 
Porter,  Brit.  Med.  Journ.,  1907. 


CHAPTER  X 

THE  BLOOD   IN   INFANCY,   OLD   AGE,   ETC. 

Infancy  and  Childhood. — Bed  Corpuscles. — At  birth  the  number  of 
red  corpuscles  is  high — on  an  average  about  6  millions  per  c.mm. 
This  condition  is  due  to  the  loss  of  fluid  which  occurs  after  birth 
by  evaporation  from  the  skin  and  respiratory  passages,  while  there  is 
little  or  no  addition  of  fluid  to  the  body  for  some  days. 

Aspiration  from  the  placenta  plays  a  part  in  determining  the 
number  of  corpuscles  in  infantile  blood,  since  they  are  more  numerous 
when  ligature  of  the  cord  has  been  delayed  than  when  it  has  been  tied 
promptly. 

The  haemoglobin  shows  a  correspondingly  high  percentage,  the  usual 
reading  being  about  120  per  cent.  This  figure  may  be  exceeded,  and 
not  infrequently  the  colour  index  tends  to  be  high  from  the  fact  that 
the  corpuscles,  like  those  of  foetal  life,  are  larger  than  in  adult  life. 
There  is  slight  variation  in  the  size  of  the  red  cells,  and  in  some 
healthy  infants  there  may  be  a  slight  degree  of  polychromasia. 

Nucleated  red  cells  (normoblasts)  are  always  present  in  the  circulat- 
ing blood  of  infants  for  some  time  after  birth.  They  are  fairly  numerous 
in  the  first  three  or  four  hours,  but  after  that  they  rapidly  diminish,  and 
are  to  be  found  only  with  great  difficulty  after  seven  days. 

The  polycythemia  soon  disappears,  and  the  ordinary  numbers  are 
reached  by  the  end  of  the  second  week. 

The  haemoglobin  percentage  also  falls,  but  the  fall  is  not  arrested 
when  it  has  reached  100  per  cent.  The  percentage  continues  to  fall 
gradually  throughout  infancy,  and  remains  about  80  per  cent,  till  the 
age  of  ten  years  is  reached,  when  it  begins  to  increase  again,  and  a  child 
of  twelve  should  have  100  per  cent. 

White  Cells. — The  leucocyte  count  at  birth  is  high,  and  frequently 
numbers  18,000  per  c.mm.  The  count  tends  to  rise  a  little  during  the 
next  two  days,  and  may  reach  30,000.  This  is  succeeded  by  a  rapid 
fall,  so  that  at  the  end  of  the  first  week  the  number  may  not  exceed 
10,000. 

S5 


86  THE   BLOOD   IN"  INFANCY,   OLD   AGE,   ETC. 

After  the  first  week  the  white  cells  again  increase.  At  eight 
months  the  number  is  about  15,000,  and  at  twelve  months  10,000. 
A  gradual  fall  continues  during  the  next  five  years.  At  six  the 
number  is  about  9000 ;  at  nine,  8000 ;  and  by  twelve  the  adult  figure 
is  reached. 

There  are  corresponding  variations  in  the  proportions  of  the  different 
cells.  The  variations  in  the  first  week  are  due  to  a  rise  and  fall  in  the 
number  of  polymorphs.  They  may  reach  a  maximum  of  70  per  cent, 
and  fall  to  20  per  cent.  During  infancy  and  early  childhood  the  rule 
is  a  high  percentage  of  lymphocytes. 

From  the  tenth  day  till  about  the  fourth  year  they  are  in  excess 
of  the  polymorphs.  About  the  tenth  day  they  constitute  60  per  cent, 
of  the  white  cells,  and  they  remain  in  about  this  proportion  till  the 
third  or  fourth  year,  when  they  fall  to  50  per  cent.  A  gradual  fall 
continues,  so  that  the  adult  proportions  are  reached  about  twelve  years 
of  age. 

The  other  white  cells  show  the  same  kind  of  variation  that  may  be 
noticed  in  the  adult,  but  there  are  no  variations  corresponding  to  age. 
If  for  any  reason  the  development  of  a  child  is  delayed  or  its  nutrition 
impaired,  the  lymphocyte  proportion  is  found  to  be  higher  than  it 
should  be  for  that  age. 

The  white  cells  in  infancy  and  childhood  are  much  more  responsive 
to  stimuli  than  in  adult  life.  During  digestion  the  increase  may  be 
very  great,  and  during  the  first  three  years  of  life  the  number  during 
fasting  may  be  doubled  or  trebled  after  a  meal. 

The  leucocytes  also  respond  more  readily  and  more  largely  to  toxic 
stimuli,  and  the  proportion  of  lymphocytes  always  tends  to  be  greater 
than  in  corresponding  conditions  in  the  adult. 

Old  Age. — There  are  no  changes  of  importance. 

Menstruation. — Slight  variations  in  the  cells  of  the  blood  and  the 
amount  of  haemoglobin  have  been  recorded.  Even  the  most  extensive 
of  the  recorded  findings  are  too  slight  to  be  of  practical  importance.1 

Pregnancy. — There  is  often  a  slight  decrease  of  red  cells  towards 
the  end  of  pregnancy  in  primiparse.     This  does  not  occur  in  multiparas 

In  many  instances,  especially  in  primiparse,  there  is  an  increase  of 
white  cells.  The  increase  becomes  noticeable  after  the  third  month, 
1  See  Polzl,  Munch,  med.  Wochenschr.,  1910,  333. 


THE  BLOOD  IN  INFANCY,  OLD  AGE,  ETC.     87 

counts  then  averaging  about  12,000.  There  is  a  gradual  increase  up 
to  the  end  of  pregnancy.  The  increase  is  shared  in  by  polymorphs 
and  lymphocytes  in  pretty  much  the  normal  proportions. 

During  labour  the  number  of  leucocytes  rises,  and  may  reach  20,000. 
The  count  falls  after  the  third  stage,  and  has  reached  normal  by  the 
end  of  the  second  week. 

Lactation. — The  blood  is  not  affected. 


CHAPTER  XI 


THE   BLOOD   IN   CERTAIN  ANIMALS 


A  great  many  observations  on  the  blood  of  the  various  domestic  and 
commonly  used  laboratory  animals  are  to  be  found  scattered  throughout 
the  magazines,  but  no  very  exhaustive  account  has  yet  been  published. 
The  following  data  are  derived  from  our  own  observations  and  from 
various  sources,  and  enough  references  are  given  to  put  any  worker  on 
the  track  of  literature  he  may  wish. 

Blood  counts  in  laboratory  animals  are  apt  to  vary  considerably 
from  different  causes.  The  differences  are  sometimes  due  to  individual 
peculiarity  or  to  differences  in  feeding  or  environment,  and  it  should 
be  remembered  that  anaemia  and  parasitic  conditions  are  common  and 
may  modify  the  blood. 


Animal. 

Observer. 

u 
p< 

Is 
Us 

go 
o 

»  c 
Dj  a 

■  e 

.sw 

■§•8 

°l 
6-1 

eucocytes  per 
c.mm. 

CS 

3  S 

s-fc? 

U 

o 

p< 

a 

1 

o 

a 

o 

1 

o 

H 

K  o 

J 

Pi 

j 

H 

w 

Horse 

Burnett. 

7,500,000 

90 

10,000 

60 

35 

4 

1 

5> 

Sabrazes. 

8,068,000 

73 

6,433 

37-5 

58 

2-5 

2-5 

5> 

Mezincesci. 

10,000 

32-60 

34-69 

2-6 

0-2 

Ox   . 

Burnett. 

6,500,000 

60 

8,000 

30 

55 

14 

1 

Sheep 

5) 

10,000,000 

7,500 

38 

60 

1-5 

0-2 

Goat 

55 

14,000,000 

12,000 

... 

Pig  . 

)J 

7,000,000 

13,000 

39 

55 

5 

1 

)5 

Giltner. 

8,450,000 

88 

19,000 

37 

56 

5-2 

1-3 

Dog 

, 

Authors. 

5,599,000 

90 

19,500 

63 

30 

7 

... 

5) 

Burnett. 

6,500,000 

10,000 

63 

25 

12 

... 

Cat 

Authors. 

8,000,000 

70 

18,000 

54 

37 

9 

... 

j) 

Burnett. 

8,000,000 

13,000 

55 

40 

5 

... 

55 

Busch  and  v. 

6,609,000 

13,330 

60 

39 

0-9 

... 

Bergen. 

Rabbit 

Authors. 

5,160,000 

74 

10,500 

43 

52 

2-5 

2-5 

)5 

Burnett. 

5,500,000 

74 

8,500 

47 

48 

3 

2 

Guinea-pig 

Authors. 

5,600,000 

100 

9,170 

37 

60 

3 

ii 

Burnett. 

5,500,000 

9,000 

47 

50 

2 

1 

Rat  . 

Authors. 

8,100,000 

110 

10,600 

28 

68 

3 

1 

Mouse 

5) 

10,850,000 

90 

5,000 

23 

71 

5-75 

0-25 

Llama 

Biffi. 

11,546,600 

10,741 

75 

22-8 

1-5 

Hedgehog  . 

Authors. 

8,800,000 

8,500 

37 

56 

6 

i 

Fowl 

5) 

3,200,000 

... 

19,000 

37 

56 

6 

1 

» 

Burnett. 

3,000,000 

25,000 

27 

65 

5 

3 

Frog 

Authors. 

500,000 

11,000 

7 

59 

27 

7 

Skate 

Fraser  Harris. 

350,000 

27,500 

... 

ss 


THE   BLOOD   IN   CERTAIN  ANIMALS 


89 


In  the  case  of  the  more  common  laboratory  animals  we  may  state 
the  extremes  which  we  have  found  in  healthy  conditions — 


<v 

o 

c 

w 

K 

QJ 

w 

,a 

>* 

Animal. 

o 
O 

"tic 
o 

s 

O 

B 

O 

s 

o 

(3 

o 

c8 

« 

w 

CW 

J 

H 

pq 

Bog        ...        . 

5,500,000 

no 

31,200 

60 

25 

14 

5» 

4,750,000 

75 

11,200 

78 

20 

2 

Cat 

8,600,000 

80 

38,800 

74 

20 

6 

» 

7,280,000 

65 

15,800 

40 

56 

4 

Babbit     . 

5,760,000 

90 

16,000 

50 

48 

1 

1 

5) 

4,560,000 

70 

7,200 

32 

62 

4 

2 

Guinea-pig 

6,880,000 

120 

21 

71 

8 

jj 

4,800,000 

90 

52 

42 

6 

The  number  of  white  cells  in  guinea-pigs  seems  to  increase  with  the 
age  of  the  animal,  as  the  following  table  indicates : — 


I. 

n. 

ill. 

IV. 

Weight 
in  grms. 

Leucocytes 
per  c.mm. 

Weight. 

Leucocytes. 

Weight. 

Leucocytes. 

Weight. 

Leucocytes. 

110 

7,400 

230 

8,400 

320 

11,200 

450 

8,800 

140 

11,600 

230 

8,000 

325 

8,200 

460 

15,400 

150 

3,000 

260 

6,400 

335 

6,600 

480 

5,800 

155 

12,400 

285 

6,600 

390 

14,000 

530 

10,400 

160 

7,800 

290 

9,000 

380 

10,200 

570 

14,800 

170 

2,400 

395 

5,600 

670 

9,600 

170 

2,600 

675 

16,400 

175 

8,800 

680 

20,400 

185 

2,800 

790 

17,000 

Average  . 

6,537 

7,680 

9,300 

13,177 

Horse  and  Ass. — Eed  corpuscles  measure  5*5  /^.  The  polymorph 
nuclei  show  an  unusual  degree  of  lobulation.  The  neutrophil  granules 
are  very  fine.  The  eosinophil  granules  are  spherical  or  ovoid  and  are 
very  large. 

Ox. — Eed  corpuscles  measure  5*6  y>.  General  morphology  does  not 
differ  greatly  from  that  of  human  blood. 

Sheep  and  Goat. — Red  corpuscles  measure  5  and  4*1  //,  respectively. 
The  neutrophil  granules  are  closer  together  and  are  very  much  smaller 


90  THE   BLOOD   IN   CEETAIN  ANIMALS 

than  in  human  polymorphs.  Kurloff's  bodies  (see  Guinea-pig)  are  fairly 
numerous  in  the  large  lymphocytes  of  the  sheep. 

Pig. — Eed  corpuscles  5'6  p  (8*5  fi  Giltner ;  6*2  ju,  Gutig).  Neutro- 
phil granules  are  very  fine. 

Dog. — Diameter  of  red  cells  7  p.  The  protoplasm  of  the  polymorphs 
has  a  slight  neutrophil  reaction,  and  prolonged  staining  is  required  to 
demonstrate  distinct  granules.  The  eosinophils  have  not  such  a  special 
affinity  for  eosine  as  for  orange.     Mast-cells  are  very  rare. 

Cat. — Eed  corpuscles  6*5  /*,.  Granules  are  present  in  the  polymorphs, 
but  they  are  exceedingly  fine  and  very  difficult  to  demonstrate.  Pro- 
longed staining  is  required  (Leishman,  half  an  hour).  The  protoplasm 
tends  to  stain  diffusely  in  the  same  tint  as  the  granules.  The  eosino- 
phils have  large  ovoid  granules.  Basophils  are  found  in  very  small 
numbers. 

Rabbit. — The  red  cells  are  poor  in  haemoglobin  and  look  anaemic. 
Average  diameter  6*5  p.  The  polymorphs  contain  large  amphophil 
granules  (pseudo-eosinophils).  There  are  also  true  eosinophils  with 
more  densely  packed  granules.  Mast-cells  are  relatively  abundant. 
Wild  rabbits  generally  give  higher  counts,  especially  of  red  cells, 
than  do  the  domestic  variety. 

Guinea-pig. — Eed  corpuscles  measure  7 '5  /x.  The  polymorphs  contain 
large  amphophil  (pseudo-eosinophil)  granules.  The  eosinophil  granules 
resemble  those  of  man,  but  they  are  divisible  into  two  groups  which 
have  somewhat  different  affinities  for  dye  stuffs.  In  many  of  the  large 
lymphocytes  there  are  large  vacuoles  which  may  be  empty,  but  which 
generally  contain  a  homogeneous  structure  which  stains  in  the  tone  of 
the  neutrophil  granules.  These  are  known  as  "  Kurloff  s  bodies."  They 
probably  consist  of  a  cellular  secretion,  but  have  been  thought  to  be 
parasites.  Schilling-Torgau  regards  them  as  chlamydozoa.  Eoss 
considers  them  to  represent  one  phase  of  the  life-history  of  a 
spirochete.1 

Bat. — The  diameter  of  the  red  cells  averages  5'8  p.  The  polymorphs 
contain  rather  scanty  and  fairly  large  granules.  Many  of  both  poly- 
morphs and  eosinophils  have  ring-shaped  nuclei. 

White  Mouse. — Eed  corpuscles  measure  5'6  /*.  The  lymphocytes  are 
mostly  large,  with  relatively  large  nucleus  and  faintly  basophil  proto- 
plasm, which  contains  a  good  many  azurophil  granules.  The  poly- 
morphs are  usually  stated  to  be  non-granular,  but  it  is  possible  with 
prolonged  staining  to  demonstrate  fine  and  very  scanty  neutrophil 
1  For  references  to  literature,  see  Folia  Hcematologica,  xii.  xiii.  Gentralbl. 


THE   BLOOD   IN   CERTAIN  ANIMALS  91 

granules.  These  cells  are  very  labile.  In  the  eosinophils  the  granules 
are  often  scanty  and  may  be  arranged  in  patches.  Eing-shaped 
nuclei  occur,  and  unless  films  are  carefully  spread  the  poly- 
morphs, whose  granules  are  often  unstained,  may  be  mistaken  for 
lymphocytes. 

Hedgehog. — Eed  cells  measure  about  4*5  /*.  The  fine  basophil  granu- 
lation of  the  lymphocytes  is  very  distinct.  The  polymorphs  have  distinct 
granules.  There  are  about  1  per  cent,  of  basophil  myelocytes.  The 
granules  in  some  of  them  are  very  large. 

Fowl. — The  great  majority  of  the  red  cells  are  oval  and  nucleated 
with  a  long  diameter  of  11*2  //,.  A  few,  however,  are  round,  and  in  these 
the  nucleus  shows  a  wider  chromatin  network.  These  cells  correspond 
to  the  large  nucleated  red  cells  of  mammalian  blood,  and  are  probably 
younger  cells  than  those  with  oval  nuclei.  Even  earlier  forms  are  found 
in  the  circulation.  These  are  oval,  nucleated,  but  non-hsemoglobin-con- 
taining  corpuscles.  They  are  usually  smaller  than  the  ordinary  forms. 
They  are  the  youngest  type  of  cell.  Again,  a  few  old  cells  are  to  be 
found  whose  nuclei  have  disappeared.  The  white  cells  are  peculiar. 
There  are  lymphocytes  and  eosinophils  resembling  those  of  mammalian 
blood.  There  are  no  ordinary  neutrophils.  Their  place  is  taken  by 
polymorphonuclear  cells,  whose  protoplasm  contains  a  large  number  of 
rod-shaped  crystalline  bodies  with  a  marked  affinity  for  eosine.  Baso- 
phils are  present  in  considerable  numbers.  They  are  myelocytes  with 
a  relatively  small  pale  nucleus  and  a  pale  protoplasm,  in  which  the 
scanty  basophil  granules  varying  in  size  are  to  be  seen.  Blood-plates 
are  absent.  Small  lipoid  bodies  (hsemoconia)  are  to  be  found  in  small 
numbers. 

Frog. — The  red  cells  have  to  some  extent  the  same  general 
characters  as  those  of  the  fowl.  The  typical  cell  is  flattened,  oval, 
and  biconvex,  with  a  thickened  equatorial  area.  There  is  an  oval 
nucleus.  The  long  diameter  measures  22  \x.  Young  forms  are  also 
found.  These  are  small  oval  cells  without  haemoglobin,  and  round 
haemoglobin-containing  cells  with  the  megaloblastic  type  of  nucleus. 
Non-nucleated  forms  occur  with  rather  greater  frequency  than  in 
the  fowl.  The  white  cells  are  lymphocytes,  polymorphs,  often  with 
fragmented  nuclei  and  without  granules,  eosinophils,  and  basophil 
myelocytes. 


92 


THE   BLOOD   IN   CERTAIN   ANIMALS 


1.  Burnett 

2.  schifone 


3.  Klieneberger        and 

Carl 

4.  Gulliver     . 


5.  Walker 

6.  Bezancon  et  Larbe     . 

7.  HlRSCHFELD. 

8.  Furno  .... 

9.  Mezincesci  . 

10.  Loewit 

11.  Levaditi 

1 2.  Tallqvist-Willebrand 

13.  Busch  and  v.  Bergen  . 

14.  D  arson 

15.  Hesse  .... 

16.  Brinckerhoff        and 

Tyzzer 

17.  Proscher     . 

18.  Kanthack  and  Hardy 

19.  Durham       .        . 

20.  Jolly  and  Stini 

21.  Bidault 

22.  Sabrazes,       Muratet, 

and  durroux 

23.  ZlETSCHMANN 

24.  Walter 

25.  Meier  .... 


Literature. 

Clinical  Pathology  of  the  Blood  of  Domesticated 

Animals,  Ithaca,  N.Y.,  1908. 
Contribute  alia  morpJiologia  comparata  dei  leucociti, 

Naples,  1907  (see  also  Folia  Hcematologica, 

1908,  Bd.  vi.  p.  422). 
Blood  Morphology  in  Laboratory  Animals,  John 

Ambros  Barth,  1912. 
Proc.  Zool.  Soc.  London,  1875,  vol.  xliii.  p.  474 

(Observations  on  the  size  and  shape  of  the 

red  corpuscles  of  vertebrates). 
Journ.  Med.  Research,  Boston,  1904,  vol.  xiii. 

p.  61  (Red  corpuscles  of  vertebrates). 
TraiU  d'Hematol.   (Leucocyte  counts  in    the 

guinea-pig,  rabbit,  dog,  cat,  and  horse). 
Virchow's  Archiv,  1897,  p.  22  (Leucocytes  in 

horse,  sheep,  goat,  ox,  pig,  rabbit,  guinea- 
pig,  rat,  mouse,  dog,  and  cat). 
Folia  Hcematologica,  xi.  Archiv,   1911,  p.  219 

(Leucocytes  in  laboratory  animals). 
Arch,  de  med.  exper.  et  d'anat.  path.,  1902,  xiv. 

p.    562  (Leucocytes   in   dogs,   guinea-pigs, 

and  white  mice). 
Folia  Hcematologica,  1907,  iv.p.  473  (Leucocytes 

of  cat,  rabbit,  and  guinea-pig). 
Virchow's  Archiv,  clxxx.  (Monkey). 
Scand.  Ark.  Physiol,  1899  (Dog  and  rabbit). 
Journ.  Med.  Research,  1903,  p.  250  (Dog  and 

cat). 
Journ.  of  Physiol.,  1900  (Dog). 
Virchow's  Archiv,  1902  (Rabbit). 
Journ.  Med.  Research,  1902,  vii.  p.  173  (Rabbit). 

Ibid.,  vii.  p.  107  (Rabbit). 
Journ.  of  Physiol.,  1894  (Rabbit). 
Journ.  of  Path,  and  Bad.,  1894  (Rabbit). 
Compt.  rend.  Soc.  de  biol.,  1905  (Red  cells  and 

blood  mass  in  white  rat). 
Arch,  de  mSd.  expir.  et  d'anat.  path.,  1904,  xvi. 

(Horse). 
Gaz.   hebd.   d.   Soc.    med.   de    Bordeaux,   1908 

(Horse). 
Internal.  Monatschr.  f  Anat.  u.  Physiol.,  1905 

(Horse). 
Pfluger's  Archiv,  cxxiii.  (Horse). 
Zeitschr.  f.  Tiermedizin,  1906,  x.  (Horse). 


THE   BLOOD    IN   CEBTAIN  ANIMALS 


93 


26.  Funke. 

27.  Gasse  . 

28.  Utendorfer 

29.  Biffi    . 

30.  Gutig  . 

31.  GlLTNER 

32.  Grunberg 

33.  Kasarinoff 

34.  CULLEN 

35.  Meinertz 


36.  "Werzberg    . 

37.  Pappenheim 

38.  Pappenheim 

39.  Freidson 

40.  Sabrazes  et  Muratet  , 

41.  Treves 

42.  Jordan  and  Flippini  . 

43.  Harris 

44.  Kawitz 

45.  Knoll  .        .        .        . 

46.  Werzberg    . 

47.  Dezewina    . 

48.  Delage 

49.  Hardy. 

50.  Bryce  . 

51.  Fry      . 


Monatsch.  f.  pract.  Tierheilh.,  1907  (Horse). 
Ibid.  (Horse). 

Archivf.  wissenschf.  u.  pract.  Tierheilh.  (Ox). 
Arch,  de   Fisiol.,    1906;     Folia   Hcematologica, 

Supplement,  1906,  iv.  (Llama). 
Arch.f.  mikr.  Anal,  1907,  p.  629  (Pig). 
Joum.  Compar.  Anat.  and  Therap.,  1907,  p.  18 

(Pig)- 

Virchow's  Archiv,  1901,  p.  303  (Leucocytes  in 
birds,  amphibians,  and  reptiles). 

Folia  Hcematologica,  Archiv,  x.  (Birds). 

Johns,  Hopkins  Hosp.  Bulletin,  1903  (Leucocytes 
of  birds  and  fishes). 

Virchoufs  Archiv,  1902,  p.  353  (Leucocytes 
in  reptiles,  fish,  crustaceans,  insects,  and 
worms). 

Folia  Hcematologica,  Archiv,  1911  (Compara- 
tive hematology  of  cold-blooded  animals). 

Virchow's  Archiv,  1896,  p.  587  (Amphibians). 

Ibid.,  1899,  p.  19  (Eed  marrow  of  amphi- 
bians). 

Arch.  f.  mikr.  Anat.,  lxxiv.  p.  435  (Amphibian 
blood). 

Folia  Hcematologica,  1908,  Bd.  vi.  pp.  167  and 
171  (Torpedo  and  Axolotl). 

Ibid.,  1911,  lxxvii.  (Eed  corpuscles  in 
amphibia). 

Folia  Hcematologica,  Archiv,  1913,  xv.  p.  1 
(Turtle). 

Joum  of  Physiol.,  1904,  p.  319  (Counts  in  Eaja 
batis). 

Arch.f.  mikr.  Anat.,  1899  (Fish). 

Sitzungsber.  der  Wiener  Akademie,  1896 
(Fish). 

Folia  Hcematologica,  Archiv,  xi.,  1911  (Fish). 

Arch.  dAnat.  micros.,  1911  (Fish). 

Arch,  de  zool.  exp6r.,  1881,  lmre-  series,  tome  ix. 
p.  166  (Crustacean  blood). 

Joum.  Physiol.,  1892,  xiii.  p.  165  (Crustacean 
blood). 

Trans.  Royal  Soc.  Edin.,  1904,  pp.  291  and 
435  (Morphology  of  the  blood  and  hsemato- 
genesis  in  lepidosiren). 

Folia  Hcematologica,  1909,  viii.  p.  467  (Blood- 
platelets  and  the  coagulation  of  the  blood 
in  the  marine  chordata — numerous  refer- 
ences). 


94  THE   BLOOD   IN   CERTAIN  ANIMALS 

52.  Pappenheim  .         .     Folia  Hcematologica,  1909,  viii.  p.  504  (Theo- 

retical considerations  regarding  comparative 
leucocyte  morphology). 

53.  Tait      ....     Quart.  Journ.  of  Exp.  Phys.,  1910,  iii.  (Coagula- 

tion in  Crustacea). 

54.  Dakin  ....     Biochem.  Journ.,  1908  (Cryoscopy  in  animals). 

55.  Atkins  .         .         .     Ibid.,  1910  (Cryoscopy  in  animals). 


CHAPTER  XII 

SOURCES   OF  THE   BLOOD-CELLS.     THE    BONE-MARROW 
AND   ITS  REACTIONS 

Sources  of  the  Blood-Cells. — The  sources  of  the  blood-cells  are  the 
lymphoid  tissues  throughout  the  body,  and  the  bone-marrow.  The 
former  supply  only  lymphocytes,  and  even  this  function  is  shared 
largely  by  the  marrow.  The  structure  of  the  lymphoid  tissues  is  simple 
and  (so  far  as  their  effect  on  the  blood  is  concerned)  the  changes  which 
they  undergo  in  disease  may  be  regarded  as  hyperplasia  and  atrophy. 
The  marrow,  on  the  other  hand,  has  a  more  complicated  structure,  and 
is  subject  to  diverse  and  profound  alterations. 

Structure  of  Bone-Marroio. — 1.  Foetal  Marrow. — In  early  foetal  life 
the  bone-marrow  consists  of  the  embryonic  mucous  tissue  which  when 
ossification  begins  invades  the  cartilage  of  long  bones  or  the  fibrous  tissue 
which  precedes  the  fiat  bones. 

This  tissue  is  invaded  by  primitive  leucocytes  and  nucleated  red 
cells  in  the  third  month  of  foetal  life.  These  cells  form  little  islands 
of  leucoblastic  or  erythroblastic  tissue  which  extend  and  may  meet  each 
other.  Very  soon  fat  is  deposited  in  the  young  fibrous  tissue,  and  this 
mixture  of  fat-cells,  red  cells,  and  white  cells  constitutes  the  red  bone- 
marrow. 

2.  Yellow  Marrow. — After  foetal  life  the  amount  of  bone-marrow 
is  greater  than  the  requirements  of  blood  formation  in  health.  The 
hsemopoietic  function  of  the  marrow  in  the  shafts  of  the  long  bones  is 
lost  and  it  becomes  yellow  marrow.  This  consists  merely  of  fatty 
fibrous  tissue,  but  as  at  any  time  in  disease  the  yellow  marrow  may 
resume  its  blood-forming  functions,  it  remains  of  potential  heemopoietic 
interest. 

3.  Reel  Marrow. — The  red  bone-marrow  occupies  the  flat  bones  and 
the  extremities  of  the  long  bones.  It  is  the  sole  source  of  the  red  cells 
and  the  main  source  of  the  white  cells  in  post-natal  life. 

The  red  marrow  has  a  supporting  framework  of  fibrous  tissue 
forming  a  reticulum  and  containing  a  large  number  of  fat-cells. 


96  SOUECES   OF  THE   BLOOD-CELLS 

Wide  thin- walled  capillaries  or  sinusoids  traverse  this  reticulum, 
anastomosing  freely  with  each  other  and  opening  directly  "into  the 
spaces  in  which  the  marrow-cells  lie. 

Some  observers  have  sought  to  show  that  the  cells  forming  red  cells 
are  intravascular,  while  the  leucocytic  areas  are  extravascular.  We 
cannot  find  evidence  of  this  on  histological  grounds. 

Between  the  fat-cells  are  great  numbers  of  blood-cells.  Bed  and 
white  cells  are  in  about  equal  proportions  and  are  indiscriminately 
mixed.  Areas  consisting  exclusively  of  one  variety  of  cell  are  very 
small.  A  large  proportion  of  the  red  cells  are  nucleated  (normoblasts) 
and  there  are  a  few  megaloblasts.  There  are  also  a  few  erythroblasts 
without  haemoglobin. 

All  the  varieties  of  leucocytes  met  with  in  the  blood  are  to  be  found  in 
the  bone-marrow.  The  most  abundant,  however,  is  the  myelocyte,  which 
does  not  normally  escape  into  the  circulation.  The  proportion  of  myelo- 
cytes (neutrophil,  eosinophil,  and  basophil)  to  each  other  is  much  the  same 
as  that  of  the  polymorphonuclear  forms  in  the  blood.  More  primitive 
types  (pro-myelocytes  and  undifferentiated  lymphocytes)  are  also  present 
in  smaller  numbers.  Ordinary  lymphocytes  are  found  to  the  extent  of 
about  20  per  cent.     Polymorphs  do  not  exceed  10  per  cent. 

A  striking  cell  found  in  small  numbers  is  the  giant  cell  (megakaryo- 
cyte). This  cell  may  measure  over  30  //.  in  diameter.  Its  protoplasm 
is  acidophil ;  the  nucleus  is  convoluted  and  basket-shaped.  The  latter 
often  appears  horseshoe-shaped  in  section,  and  consists  of  several 
little  rounded  masses  with  fine  connections. 

This  cell  should  not  be  confused  with  the  multinucleated  osteoclast 
found  in  connection  with  developing  bone  (Plate  IV.). 

Bone-Marrow  Reactions  and  Degenerations. — The  bone-marrow  very 
readily  responds  to  different  stimuli.  The  stimulus  may  be  such  that 
there  is  special  activity  on  the  part  of  the  red  cells  (erythroblastic 
reaction)  or  on  the  part  of  the  white  cells  (leucoblastic  reaction).  Both 
may  be  present  at  the  same  time.  In  these  processes  the  marrow 
becomes  more  vascular,  and  the  reaction  may  extend  into  the  yellow 
marrow  in  the  shafts  of  the  long  bones.  The  haemopoietic  cells  increase 
at  the  expense  of  the  fat-cells,  and  if  the  activity  be  considerable  the 
spicules  of  cancellous  bone  and  the  walls  of  compact  bone  may  be 
partly  absorbed  to  make  more  room. 

Erythroblastic  Reaction. — This  is  of  two  kinds — normoblastic  and 
megaloblastic. 

1.  Normoblastic. — The   marrow  becomes  more    vascular   and   there 


Plate  IV. — Normal  Red  Marrow. 

a.  A  group  of  red  corpuscles  and  normoblasts,  one  in  mitosis. 

'/.  A  group  of  neutrophil  leucocytes,  myelocytes  and  polymorphs. 

a.   An  eosinophil  myelocyte  and  polymorph. 

d.  A  giant  cell.     Immediately  above  it  are  two  lymphoctyes  and  a  fat-cell. 


A.  G.,  fecit. 


SOUECES   OF  THE   BLOOD-CELLS  97 

may  be   extension  of  hemopoietic  function  into  the  yellow  marrow, 
which  becomes  red. 

On  microscopic  examination  there  is  a  great  increase  in  the  number 
of  erythrocytes  and  normoblasts,  and  many  of  the  latter  show  mitotic 
figures.  In  most  cases  there  is  concomitant  activity  on  the  part  of  the 
myelocytes,  but  where  the  stimulus  is  long  continued  the  white  cell 
activity  may  subside,  and  in  such  cases  the  majority  of  the  white  cells 
are  lymphocytes.  This  state  of  affairs  indicates  a  certain  degree  of 
marrow  exhaustion,  as  might  be  inferred  from  the  comparative  fre- 
quency with  which  it  is  found  in  the  post-mortem  room.  Normoblastic 
bone-marrow  reaction  is  found  most  typically  after  hemorrhage. 

2.  Megaloblastic. — In  this  condition  the  marrow  is  very  red  and  all 
the  yellow  marrow  in  the  body  may  be  transformed  to  active  hemo- 
poietic tissue.  The  reaction  is  probably  always  due  to  disturbance  of 
the  marrow  itself  and  is  not  a  mere  response  to  a  demand  for.  an 
increased  output  of  red  corpuscles.  The  microscope  reveals  a  picture 
of  remarkable  activity.  Megaloblasts  are  found  in  enormous  numbers, 
and  a  very  large  proportion  of  them  show  mitotic  figures. 

The  reaction  is  often  associated  with  myelocytic  activity,  but  in 
perhaps  40  per  cent,  of  cases  lymphocytes  preponderate  among  the 
white  cells.  Megaloblastic  bone-marrow  is  typically  found  in  pernicious- 
anemia. 

Zeucoblastic  Reaction. — In  response  to  various  stimuli  there  may  be 
great  activity  of  the  white  cells.  The  causes  are  those  which  bring 
about  leucocytosis  in  the  peripheral  circulation,  and  the  stimulus  may 
specially  affect  one  or  more  of  the  different  varieties. 

The  cells  most  commonly  affected  are  the  neutrophil  myelocytes. 
When  the  reaction  is  severe  a  large  amount  of  yellow  marrow  may  be 
involved,  and  owing  to  increased  vascularity  it  becomes  red  in  colour,, 
though  not  so  red  as  in  the  erythroblastic  reaction. 

Myelocytes,  and  to  a  certain  extent  their  non-granular  precursors, 
are  actively  dividing.  There  is  no  accumulation  of  polymorphs  in  the 
marrow,  since  they  are  hurried  into  the  circulation,  in  many  cases  even 
before  they  are  mature. 

Certain  toxins  bring  about  special  activity  on  the  part  of  the- 
eosinophils  or  basophils,  either  alone  or  along  with  neutrophils. 

In  children  and -in  a  few  diseases  there  is  special  activity  on  the- 

part  of  the  lymphocytes. 

-  The  special  marrow  conditions  associated  with  leukemia  will  be 

discussed  in  connection  with  that  disease. 

7 


98  SOUECES   OF  THE  BLOOD-CELLS 

It  is  to  be  noted  that  while  special  erythroblastic  activity  is  usually 
associated  with  leucoblastic  activity,  the  reverse  (if  we  exclude 
leukaemia)  does  not  occur. 

Another  point  which  deserves  passing  notice  is  the  fact  that  the 
peripheral  blood  does  not  always  reflect  the  condition  of  the  marrow. 
Thus  we  may  find  an  abundant  polymorph  leucocytosis  before  death, 
yet  polymorphs  may  be  very  scanty  in  the  marrow.  The  explanation 
here  is  probably  that  suggested  above,  viz.  that  the  polymorphs  are 
turned  out  as  soon  as  they  are  ripe,  and  there  may  be  a  special 
emigration  just  before  death. 

A  more  puzzling  state  of  affairs  is  the  condition  often  found  in 
pernicious  ansemia  in  which  the  marrow  of  cases  showing  a  marked 
diminution  of  polymorphs  in  the  circulation  is  found  to  present  a 
picture  of  remarkable  myelocytic  activity. 

Bone-Marrow  Degenerations — Fatty  Degeneration. — In  this  condition 
there  is  a  diminution  in  the  number  of  hsemopoietic  cells,  and  only 
small  islands,  consisting  mainly  of  lymphocytes,  are  seen  at  intervals 
separated  by  several  fat-cells. 

The  condition  is,  of  course,  not  primarily  a  fatty  degeneration,  but 
is  a  phase  of  exhaustion  of  the  blood-forming  cells.  It  is  brought  about 
(1)  by  severe  toxsemias  which  overwhelm,  rather  than  stimulate,  the 
marrow ;  (2)  by  repeated  or  continuous  hsemorrhage,  as  in  some  cases 
of  haemophilia  and  purpura ;  (3)  it  occurs  in  aplastic  ansemia. 

Fibroid  Degeneration. — The  reticulum  is  thickened,  and  there  may 
be  increase  in  the  fibrous  tissue  to  such  an  extent  as  to  diminish  the 
amount  of  hsemopoietic  tissue.  The  degeneration  occurs  in  old  age,  in 
cases  of  debility,  and  in  syphilis. 

Gelatinous  Degeneration. — This  condition  may  occur  as  a  primary 
change  in  cases  of  inanition,  but  much  more  commonly  it  represents 
a  phase  of  marrow  exhaustion  after  severe  stimulation.  Stockman  and 
Charteris 1  found  that  it  followed  great  marrow  activity  in  animals  after 
prolonged  administration  of  lead,  mercury,  and  arsenic.  It  also  occurs 
in  toxsemias  due  to  infection  or  malignant  disease.  The  naked-eye 
appearance  of  the  marrow  varies  with  the  condition  preceding  it,  as  it 
may  supervene  in  a  fatty  marrow  or  in  a  marrow  actively  leucoblastic 
or  erythroblastic.  There  is  always  a  somewhat  glistening  homogeneous 
appearance,  with  increased  translucency.  The  microscopic  change 
consists  in  an  absorption  of  the  fat-cells,  whose  capsules  may  appear 
shrivelled.  The  blood-forming  cells  also  disappear,  so  that  the  cells 
1  Joum.  of  Path,  and  Bad.,  ix.  1903. 


SOUECES   OF  THE   BLOOD-CELLS  99 

and  fibres  of  the  reticulum  become  unusually  conspicuous,  and  give  a 
curious  fibrillated  appearance  to  some  sections.  In  others,  possibly 
representing  an  earlier  stage  before  the  fat  is  completely  absorbed,  the 
marrow  appears  unusually  homogeneous.  The  blood-forming  cells  are 
found  in  somewhat  widely  scattered  areas.  The  kind  of  cell  which 
preponderates  is  usually  the  lymphocyte  with  the  representatives  of  the 
cellular  activity  before  the  gelatinous  change  supervened. 


CHAPTER  XIII 
DEVELOPMENT  OF  THE   CELLS   OF  THE   BLOOD 

Development  and  Eelationship  of  Leucocytes 

Lymphocytes. — We  regard  the  whole  of  the  hyaline  series — large  lympho- 
cytes, small  lymphocytes,  large  mononuclears,  and  so-called  transitionals 
— as  belonging  to  one  large  class,  which  may  be  called  lymphocytes, 
lymphoid  cells,  or  lymphoidocytes,  as  may  hereafter  be  found  most 
desirable.     The  reasons  on  which  we  base  this  view  are  as  follows : — 

1.  Since  Wolff  discovered  the  azurophil  granules  in  lymphocytes 
we  have  made  countless  observations  on  their  incidence  in  normal  and 
abnormal  conditions  and  we  have  found  them  in  every  form  of  the  cells 
under  discussion,  from  the  smallest  lymphocyte  to  the  largest  mono- 
nuclears and  transitionals,  and  sometimes  as  numerous  in  the  former 
as  in  the  latter.  The  ordinary  dry  method  is  not  altogether  satisfactory 
for  showing  them,  because,  as  has  been  shown,  they  are"  probably  to  a 
certain  extent  soluble  in  water  and  they  always  shrink  considerably 
in  dry  films.  The  method  which  we  have  found  most  satisfactory  for 
demonstrating  them  is  to  drop  a  film  of  blood  on  a  cover-glass,  before 
it  is  dry,  into  a  weak  solution  of  Leishman's  or  Wright's  stain 1  in  methyl 
alcohol,  and  to  leave  the  cover-glass  there  for  any  length  of  time  up 
to  half  an  hour;  then  remove  the  cover-glass,  allow  it  to  dry,  and 
mount  in  balsam.  If  the  stain  is  sufficiently  diluted  with  methyl 
alcohol  there  is  no  precipitate  on  the  surface  of  the  film,  and  the 
granules  are  exceedingly  well  brought  out  and  are  found  to  be  larger,, 
to  be  more  numerous  in  the  cells,  and  to  be  found  in  a  larger  pro- 
portion of  cells  than  in  dry  films. 

Pappenheim  believes  that  these  granules  are  not  homologous  with 
the  granules  of  the  neutrophil  and  eosinophil  series,  but  that  they  are 
in  some  way  a  secretion  product,  and  that  they  are  contained  in  the 
meshes  of  the  reticulum.  It  is  extremely  difficult  to  be  sure  whether 
this  is  the  case  or  not,  for  a  preparation  which  shows  the  granules  well 
never  shows  the  reticulum  of  the  cytoplasm  satisfactorily.  Wright's 
stain  or  any  of  the  stains  which  contain  azur  do  not  bring  out  the 
1  Jov/rn.  of  Med.  Research,  vii.  138. 

100 


DEVELOPMENT   OF  THE   CELLS   OF   THE   BLOOD     101 

reticulum  nearly  so  satisfactorily  as  Jenner's  stain  does,  but  we  have 
sometimes  seen  appearances  which  made  us  think  that  these  granules, 
like  those  of  the  other  series,  are  situated  at  nodal  points  on  the 
reticulum.  Further,  we  have  often  observed  them  in  the  small  pseudo- 
podia  which  are  thrown  out  by  the  small  and  large  lymphocytes  in 
blood.  This  is  presumably  more  likely  to  occur  if  they  are  integral 
parts  of  the  reticulum  than  if  they  are  secretion  granules. 

2.  It  has  been  definitely  shown  that  all  these  cells,  down  to  the 
smallest  lymphocytes,  are  capable  of  movement,  though  it  is,  of  course, 
the  larger  cells  of  the  class  which  move  more  actively  by  reason  of 
their  large  amount  of  cytoplasm. 

3.  The  cytoplasm  of  all  these  cells  is  basophil — intensely  so  in  the 
smaller  members  of  the  series,  less  so  in  the  larger.  At  Oxford  in 
1904  *  one  of  us  went  very  minutely  into  this  point  and  showed  that 
the  reason  for  this  difference  between  the  large  and  small  cells  is  that 
the  strands  of  the  reticulum  are  not  only  thicker  but  much  more 
tightly  packed  together  in  the  small  and  large  lymphocytes  than  in 
the  mononuclears  and  transitionals,  but  that  every  gradation  could 
be  found  between  the  terminal  members  of  the  series  in  this  respect, 
and  that  it  was  quite  common  to  find  great  variation  in  the  character 
of  the  reticulum  in  different  parts  of  the  same  cell,  especially  frequently 
in  the  cells  which  stand  intermediate  between  the  large  lymphocyte 
and  the  large  mononuclear. 

4.  Every  transition  can  be  found  between  the  round  nucleus  of  the 
large  lymphocyte  and  the  most  polymorphous  nucleus  of  the  tran- 
sitional. The  fact  that  the  nucleus  does  not  advance  further  in  poly- 
morphism is  probably  associated  with  the  fact  that  these  cells  are 
not  so  amoeboid  as  the  members  of  the  neutrophil  series.  In  some 
transitionals,  however,  the  nuclers  is  as  much  twisted  as  in  the 
ordinary  polymorph.  The  bridges  between  the  knobs  of  chromatin 
are  always  thicker.  We  have  never  seen  anything  whatever  which 
would  lead  us  to  suppose  that  there  was  any  relation  between  the 
so-called  transitionals  and  the  polymorphonuclear  neutrophils. 

5.  The  difference  in  size  in  the  cells  is  of  no  great  importance. 
It  seems  to  us  that  the  increase  in  size  in  the  large  mononuclears  and 
transitionals  is  due  largely  to  the  taking  up  of  fluid,  as  the  strands 
of  the  reticulum  are  often  widely  separated,  and  these  cells  are 
obviously  soft,  as  may  be  seen  by  the  way  in  which  they  are  indented 
in  films  by  the  red  corpuscles.     This  oedema  of  the  cells  may  make 

1  Gulland,  Brit.  Med.  Journ.,  September  1904. 


102     DEVELOPMENT   OF  THE   CELLS   OE   THE   BLOOD 

them  more  labile,  and  we  find  that  many  of  the  degenerated  lympho- 
cytes in  films  have  the  appearance  of  mononuclears  and  transitionals. 
It  is,  of  course,  quite  well  known  that  both  these  larger  members  of  the 
series  are  found  in  lymph  glands  and  also  in  lymph  from  the  thoracic 
duct  and  large  lymph  vessels. 

Beattie,1  among  others,  has  observed  many  transitional  forms  be- 
tween the  different  members  of  the  series.  Houston  2  believes  that  in 
normal  blood  it  is  fairly  easy  to  distinguish  between  the  different  forms, 
but  that  this  is  not  the  case  in  some  pathological  conditions. 

We  are  on  more  difficult  ground  when  we  attempt  to  trace  exactly 
the  relationship  between  the  different  members  of  the  series.  Pappen- 
heim  3  regards  the  large  lymphocyte  as  the  mother  cell  which  produces 
all  other  forms — red  corpuscles,  the  cells  of  the  granular  series,  and  the 
different  forms  of  lymphoid  cells ;  and  he  regards  the  small  lymphocyte 
as  being  older  than  the  large  cell  and  a  riper  form.  This  is,  of  course, 
absolutely  correct  as  regards  the  reproductive  history  of  the  cells, 
because  there  is  no  doubt  that  small  lymphocytes  are  always  produced 
by  the  mitotic  division  of  the  large  forms,  and  this  occurs  in  lymphatic 
tissue  throughout  the  body  and  in  marrow.  But  he  appears  to  con- 
sider that  the  small  lymphocytes,  when  they  are  once  formed,  are  not 
capable  of  further  development,  but  that  they  become  destroyed  in 
blood  or  tissue  in  the  same  way  that  polymorphs  are.  This  conclusion 
we  are  very  unwilling  to  accept,  for  both  in  normal  and  pathological 
blood  and  in  lymphatic  tissue  everywhere  one  finds  countless  cells 
which  it  is  impossible  to  place  with  certainty  in  one  or  other  category, 
and  it  is  difficult  to  see  whence  they  are  derived  unless  it  is  from  the 
growth  of  small  lymphocytes  and  their  conversion  into  larger  cells. 
He  cites  in  support  of  his  view  the  analogue  of  the  transformation 
of  large  megaloblasts  into  small  normoblasts,  but  this  is  really  beside 
the  mark,  because  the  ultimate  end  of  the  red  cell  is  a  non-nucleated 
non-amoeboid  corpuscle  which  has  ceased  to  be  a  cell,  and  this  cannot 
be  said  of  the  lymphocyte,  in  which,  when  degeneration  does  take  place, 
the  nucleus  is  the  last  part  to  disappear. 

It  seems  to  us  much  more  probable  that  the  ranks  of  the  large 
lymphocytes  are  reinforced  from  their  smaller  congeners,  and  that  further 
development  from  the  large  lymphocyte  may  take  place  along  two  lines, 
ending  in  the  one  case  in  a  large  mononuclear,  and  in  the  other  in  the 

1  Beattie,  Brit.  Med.  Joum.,  September  1904. 

2  Houston,  ibid. 

3  Folia  Hcematologica,  1905. 


DEVELOPMENT  OF  THE  CELLS  OF  THE  BLOOD  103 

so-called  transitional  in  accordance  with  M.  Heidenhain's x  law  as  to 
the  relative  behaviour  of  nucleus  and  centrosomes  in  leucocytes  and 
free  cells  generally.  His  conclusions  are  that  the  cytoplasm  consists 
of  a  ground  substance  in  which  are  embedded  radii  which  have  their 
centre  in  the  centrosomes,  astrosphere,  or  attraction  sphere.     When  the 


*5; 


p 


Fig.  22. — Diagram  Illustrating  the  Development  op  the  Nucleus. 

(a)  The  lymphocyte  series. 

1.  Large  lymphocyte  (large  lymphoid  cell).    2.  Daughter  (small)  lymphocytes.    3.  Typical  large 
lymphocyte  developed  by  growth  of  2.    4.   Further  development  as  large  mononuclears. 
5.  As  transitionals.    6.  Ultimate  stage  of  transitional. 
(l>)  The  neutrophil  series. 

1.  Myelocyte.  2.  Daughter  myelocytes.  3.  Young  typical  myelocyte.  4.  Myelocyte  correspond- 
ing to  large  mononuclears.  5.  Myelocyte  corresponding  to  transitionals.  6.  Polymorpho- 
nuclear neutrophil. 

(c)  Eosinphil  myelocyte  and  polymorphonuclear. 

(d)  Basophil  myelocyte  and  polymorphonuclear. 

cell  is  in  a  state  of  rest  the  pull  of  these  radii  tends  to  bring  the 
astrosphere  to  the  centre  of  the  cell.  The  usual  obstacle  is  the  nucleus, 
and  in  cells  with  a  small  amount  of  cytoplasm,  for  example  the  small 
lymphocytes,  the  pull  is  not  strong  enough  to  overcome  this  resistance. 
As  the  cytoplasm  increases  in  amount  the  pull  becomes  stronger  and 
1  M.  Heidenhain,  Arch.  f.  mikr.  Anat.,  xliii.  1894. 


104    DEVELOPMENT   OF  THE   CELLS   OF   THE   BLOOD 

the  nucleus  is  pushed  to  one  side  of  the  cell  and  ultimately  deformed, 
becoming  first  oval  and  eccentric,  then  kidney-shaped,  and  finally 
horseshoe-shaped.  At  this  stage  the  astrosphere  comes  to  rest  in  the 
centre  of  the  cell,  and  a  transitional  leucocyte  is  the  result.  In  some 
cells  the  cytoplasm  grows  out  of  proportion  to  the  nucleus,  and  the 
astrosphere  thus  reaches  the  centre  of  the  cell  without  causing  any 
nuclear  deformation.     The  result  is  a  large  mononuclear. 

"We  should  not  like  it  to  be  understood  that  these  two  sub-series 
of  lymphocytes  are  strictly  separate  from  one  another.  It  seems  to 
us  that,  within  different  series,  change  of  circumstances  may  result  in 
alteration  of  the  relations  between  nucleus  and  cell  body,  and  that 
therefore  a  large  mononuclear  may  conceivably  be  transformed  into  a 
transitional,  and  possibly  the  converse  may  also  hold.  We  have  already 
noted,  however,  that  many  of  the  most  degenerated  lymphocytes  seem 
to  be  mononuclears  and  transitionals. 

It  is  very  difficult  to  find  any  terms  which  can  be  used  instead 
of  the  objectionable  terms  "  large  mononuclears "  and  "  transitionals." 
Pappenheim's  proposal  of  "  splenocy tes "  is  unsatisfactory  for  many 
reasons.  In  the  first  place,  because  there  is  no  evidence  whatever  (and 
Pappenheim  himself  does  not  suggest  it)  that  these  cells  are  formed 
specially  in  the  spleen — in  fact  our  researches  on  that  organ 1  went  to 
show  that  the  lymphocytes  which  are  formed  in  the  spleen  are  retained 
entirely  or  almost  entirely  in  the  organ  and  do  not  pass  into  the 
blood  at  all.  And,  in  the  second  place,  there  are  many  observations 
on  record  where  the  numbers  of  these  cells  in  the  blood  remained 
unchanged  after  splenectomy.  For  example,  Houston 2  quotes  a  case 
of  splenectomy  where  the  proportion  of  large  mononuclears  was  very 
distinctly  increased,  and  Crescenzi's3  observations  go  to  show  the 
same  thing. 

The  lymphocytes  are  the  least  differentiated  of  the  leucocytes,  and 
are  found  in  many  forms  of  lower  animals  where  the  cells  of  the 
granular  series  do  not  occur  at  all.  They  are  the  first  cells  to  appear 
in  the  mammalian  embryo  (Browning 4  and  others).  They  are,  more- 
over, the  most  ubiquitous  of  the  leucocytes.  They  are  found  in  all 
parts  of  the  ordinary  lymphatic  apparatus,  in  the  blood,  and  in  the 
bone-marrow,  and  in  all  these  situations  all  the  forms  which  we  regard 

1  Paton,  Gulland,  and  Fowler,  Joum.  of  Physiol.,  1902. 

2  Houston,  Brit.  Med.  Joum.,  September  1904. 

3  Crescenzi,  Lo  Sperimentale,  1904. 

4  Browning,  Joum.  of  Path,  and  Bad.,  1905. 


DEVELOPMENT  OF  THE  CELLS  OF  THE  BLOOD  105 

as  belonging  to  the  lymphocyte  series  may  be  found,  some  preponderat- 
ing in  one  situation,  some  in  another. 

Neutrophil  Leucocytes. — These  are  known  to  start  as  leucocytes  of 
the  myelocyte  form,  that  is,  cells  generally  of  large  size  with  a  rounded 
pale-staining  nucleus  and  granules  of  the  typical  character  in  the  cell 
body.  The  myelocytes  are  found  normally  only  in  the  bone-marrow. 
In  pathological  conditions  myelocytes  may  be  found,  not  only  in  the 
marrow  but  in  all  the  hemopoietic  organs,  including  the  liver.  This 
myelocyte  form  divides  by  mitosis ;  the  resulting  cell  is  rather  smaller 
than  the  mother  myelocyte,  but  otherwise  similar  in  character.  It 
grows  by  enlargement  both  of  the  nucleus  and  of  the  cell  body,  and  its 
nucleus  may  remain  rounded,  especially  in  cases  where  the  cell  body 
rapidly  increases  in  size,  or  may  become  indented,  kidney-shaped,  and 
ultimately  horseshoe-shaped  or  even  ring-shaped.  The  nucleus  of  the 
ripe  neutrophil  cell  may  assume  almost  any  shape,  and  it  has,  more- 
over, a  tendency  to  be  made  up  of  knobs  of  chromatin  joined  together 
by  narrow  bridges.  We  would  remark,  however,  that  our  ordinary 
methods  of  film  preparation  make  the  narrowness  rather  more  marked 
than  it  should  be.  Wet  preparations  made  by  our  sublimate-alcohol- 
ether  method,  or  in  other  ways,  show  a  much  more  compact  nucleus  as 
a  rule,  with  thicker  bridges  between  the  knobs. 

This  progression  from  the  rounded  form  to  the  polymorphous 
nucleus  is  in  full  accordance  with  M.  Heidenhain's  law  as  explained 
in  relation  to  the  lymphocyte  series.  As  the  centrosome  is  pulled 
towards  the  centre  of  the  cell,  the  nucleus  is  pushed  to  one  side  and 
ultimately  deformed,  becoming  first  oval  and  eccentric,  then  kidney- 
shaped,  and  finally  horseshoe-shaped.  At  this  stage  the  astrosphere 
comes  to  rest  in  the  centre  of  the  cell,  and  even  with  ordinary  methods 
the  clear  space  free  from  granules,  which  represents  the  astrosphere,  can 
often  be  seen  lying  in  the  hollow  of  indented  or  kidney-shaped  nuclei. 
In  some  cells  the  cytoplasm  grows  out  of  proportion  to  the  nucleus, 
and  the  astrosphere  thus  reaches  the  centre  of  the  cell  without 
causing  any  nuclear  deformation.  Many  of  the  large  myelocytes 
have  this  shape. 

We  have  been  accustomed  to  consider  that  after  a  cell  with  a  horse- 
shoe-shaped or  ring-shaped  nucleus  begins  to  move  the  nucleus  moves 
with  it,  and  may  be  secondarily  deformed,  and  the  more  amoeboid  the 
cell  the  greater  is  the  deformation  likely  to  be.  For  this  reason  the 
nuclei  of  the  neutrophil  polymorphous  form  were  supposed  to  be  so 
much  more  deformed  than  those  of  the  eosinophil  polymorphous  form, 


106     DEVELOPMENT   OF   THE   CELLS   OF   THE   BLOOD 

because  they  are  more  actively  amoeboid.  But  a  very  acute  paper  by 
Pappenheim1  puts  this  process  in  another  light,  and  gives  a  much 
better  explanation.  He  points  out  that  polymorphism  of  the  nucleus 
is  not  an  expression  of  the  power  of  locomotion,  nor  of  active  kinetic 
locomotion,  as  on  the  one  hand  mononuclear  cells  may  also  be  amoeboid 
and  remain  mononuclear  during  that  process.  Such  cells  are  the  mast- 
cells  of  connective  tissue,  the  primary  wandering  cells,  the  small 
lymphocytes  of  the  blood,  and  others.  On  the  other  hand,  poly- 
morphous nuclei  remain  polymorphous  when  the  cell  is  entirely  at 
rest,  as  in  the  ordinary  neutrophils  of  the  blood.  The  myelocytes  are; 
also  mobile,  but  the  changes  in  the  nucleus  produced  during  their 
movements  are  quite  different  from  polymorphous  nuclei.  Poly- 
morphism is  really  an  internal  plastic  process,  the  expression  of  a 
change  in  the  internal  structure  of  the  cell,  and  really  a  process  of 
ripening.  He  agrees  with  the  observations  of  M.  Heidenhain,  which 
we  have  already  cited.  We  would  be  inclined  to  go  a  step  further  and 
to  consider  that  the  nucleus  becomes  polymorphous  in  order  that  the 
cell  may  become  more  actively  amoeboid.  There  is  ample  evidence 
that  the  power  of  amoeboid  movement  lies  in  the  cytoplasm  and  that 
the  nucleus  is  passive,  and,  indeed,  except  for  its  relation  to  the  life 
of  the  cell,  rather  a  hindrance  to  movement.  Therefore  the  more  the 
nucleus  is  broken  up  into  lobes  with  narrow  bridges  between  them 
the  easier  will  it  be  for  the  cytoplasm  to  drag  it  through  narrow 
openings. 

Pappenheim  also  considers  that  these  changes  of  plastic  ripening 
cannot  be  turned  back,  and  that  though  in  suppuration  and,  for  instance, 
in  sputum  one  often  finds  mononuclear  neutrophil  and  eosinophil  forms, 
these  are  easily  distinguished  from  normal  mononuclear  forms  or 
myelocytes. 

The  actual  form  of  the  neutrophils  varies  in  different  animals,  and 
perhaps  in  relation  to  mammalia  generally  it  would  be  better  to  use 
the  term  "oxyphil"  rather  than  neutrophil.  They  are  confined  to 
warm-blooded  animals. 

Eosinophils. — The  eosinophils  also  start  as  myelocytes.  These  are 
found  in  the  bone-marrow,  but  also  to  a  certain  extent  in  connective 
tissue,  thymus,  lymphatic  glands,  and  elsewhere,  though  it  is  doubtful 
whether  they  multiply  in  these  situations  to  any  very  great  extent.  Like 
the  neutrophils  they  may  be  found  in  any  of  the  hemopoietic  organs 
in  pathological  conditions. 

1  Pappenheim,  Folia  Hcematologica,  ii.  1905. 


DEVELOPMENT   OE   THE   CELLS   OE  THE   BLOOD     107 

The  series  is  phylogenetically  next  in  age  to  the  lymphocytes,  and 
one  finds  that  these  cells  appear  in  many  cold-blooded  animals,  and 
that  they  occur  in  mammalian  embryos  at  a  date  not  very  much  later 
than  the  lymphocytes  but  long  before  the  neutrophil  series.  They 
are  not  quite  so  ubiquitous  as  the  lymphocytes,  but  they  are  certainly 
found  with  great  frequency  in  connective  tissue  without  any  very 
evident  reason  for  their  presence,  and  it  seems  probable  that  they 
may  multiply  in  these  situations,  from  the  fact  that  myelocyte  forms 
are  often  found.  They  are  probably  produced  mainly  in  the  bone- 
marrow,  because  it  has  been  shown  that  in  cases  where  there  is  a 
marked  blood  eosinophilia  the  number  of  myelocyte  forms  in  the 
marrow  is  very  greatly  increased ;  but  they  seem  capable  of  consider- 
able adaptation  to  other  conditions,  and  in  cases  where  the  marrow 
is  rendered  unsuitable  for  their  proliferation,  as  in  some  lymphatic 
leuksemias,  they  are  found  in  numbers  in  the  spleen,  liver,  and  else- 
where, sometimes  in  company  with  neutrophil  myelocytes,  but  much 
more  frequently,  and  apparently  earlier,  without  them. 

In  these  two  granular  series  it  is  to  be  noted  that  only  the  final 
polymorphonuclear  forms  are  to  be  found  in  the  blood  in  normal  con- 
ditions. All  the  precursors  of  that  stage  are  found  normally  only  in 
the  marrow,  with  the  possible  exceptions  in  the  case  of  the  eosinophils 
already  noted.  It  is  fully  agreed  that  a  demand  for  polymorphs  of 
either  of  these  series  in  the  blood  or  in  the  tissues  results  in  an  increase 
in  the  number  of  myelocyte  forms  in  the  marrow,  and  if  the  demand 
for  cells  is  sufficiently  great,  results  in  an  increase  in  the  amount  of 
functional  marrow. 

Basophils. — With  regard  to  the  basophil  series  the  evidence  is  not 
quite  so  complete.  These  forms  are  very  scanty  in  either  normal  or 
pathological  blood,  with  the  single  exception  of  splenomedullary  leuk- 
aemia and  a  few  other  conditions  in  which  experimentally  it  has  been 
shown  that  they  can  be  increased.  The  presence  of  myelocyte,  forms 
in  the  marrow  and  polymorphonuclear  forms  in  the  blood  makes  one 
conclude  that  their  development  is  along  similar  lines  to  that  of  the 
other  granular  cells. 

The  Relation  of  Leucocyte  Forms  to  One  Another. — From  what 
has  just  been  said  with  regard  to  the  ancestral  character  of  the  lympho- 
cyte and  from  all  that  is  known  of  its  history  it  is  obvious  that  it  is  the 
primary  form  of  all  leucocytes,  so  far  at  least  as  embryonic  life  is  con- 
cerned.    An  immense  amount  of  discussion  has  raged  over  the  question 


108     DEVELOPMENT   OE   THE   CELLS   OF   THE   BLOOD 

as  to  whether  the  same  can  be  said  of  lymphocytes  in  post-embryonic 
life — whether  they  form  an  absolutely  independent  series  or  whether 
the  other  series  spring  from  them.  From  everything  that  is  known 
with  regard  to  the  facts  of  chemiotaxis  and  leucocyte  response  we 
think  one  must  conclude  that  for  practical  purposes  the  different  series 
are  kept  apart  in  adult  life.  Under  ordinary  conditions  certainly 
mitotic  reproduction  of  myelocyte  forms  is  quite  sufficient  to  supply 
ordinary  needs. 

Much  has  been  written  about  the  occurrence  of  eosinophils  and 
neutrophil  myelocytes  with  basophil  cytoplasm  {'promyelocytes),  and 
these  have  constantly  been  quoted  as  transitions  from  lymphocytes  to 
the  other  forms.  We  think  it  would  be  impossible  for  us  to  deny  the 
possibility  of  such  a  thing  occurring.  What  has  happened  in  embryonic 
life  may,  under  certain  conditions,  occur  again.  The  existence  of  per- 
nicious ansemia  is  a  sufficient  answer  to  the  objections  to  this  view,  but 
it  must  also  be  remembered  that  in  judging  of  the  nature  of  these  cells 
all  young  cells  tend  to  have  basophil  cytoplasm,  and  these  forms  may 
be  simply  freshly  formed  myelocytes. 

There  is  a  strong  tendency  at  the  present  time  to  distinguish  the 
primitive  cells  of  the  granular  series  (myeloblasts)  from  those  of  the 
lymphocyte  series.  The  distinction  is  based  upon  the  nuclear  char- 
acters described  on  p.  68,  the  intensely  basophil  characters  of  the 
protoplasm,  and  a  positive  oxydase  reaction.  From  the  developmental 
aspect  the  point  is  not  of  great  importance,  since  (as  Muir  puts  it) 
it  is  merely  a  question  of  the  stage  at  which  characteristic  differentiation 
begins.  A  matter  of  more  importance  is  the  occurrence  of  myeloblasts 
in  leukaemia.  Here  we  are  met  with  the  difficulty  that  only  by  the 
use  of  panoptic  stains  can  the  special  characteristics  of  myeloblasts 
be  shown,  and  even  then  the  existence  of  transitional  forms  between 
lymphocytes  and  myeloblasts  will  cause  much  difficulty.  It  has 
further  been  shown  that  a  sufficiently  primitive  myeloblast  does  not 
give  the  oxydase  reaction — a  negative  characteristic  which  it  shares 
with  the  lymphocyte. 

The  Relation  of  Leucocytes  to  Red  Corpuscles. — If  one  goes  far 
enough  back  in  embryonic  life  one  reaches  a  stage  at  which  there  are 
no  true  leucocytes  and  no  true  nucleated  reds,  but  only  undifferentiated 
cells  which  may  become  either  one  or  the  other,  and  in  this  sense 
it  is  possible  to  say  that  leucocytes  and  red  cells  start  from  a  common 
origin.     One  set  of  these  cells  acquire  or  manufacture  haemoglobin  in 


DEVELOPMENT   OF   THE   CELLS   OF   THE   BLOOD     109 

their  cytoplasm  and  become  the  megalobastic  precursors  of  ordinary  red 
cells ;  the  other  sets  do  not  come  to  contain  haemoglobin  and  become 
the  precursors  of  the  leucocytes  {of.  Bryce x).  The  former  cells  multiply 
in  mammalian  embryos  with  extraordinary  rapidity,  while  the  latter 
remain  almost  stationary  in  number  for  a  long  period.  It  is  thus  easy 
to  find  stages  in  development  at  which  the  nucleated  red  cells  out- 
number the  leucocytes  in  the  embryonic  body  by  thousands  to  one,  and 
where  the  red  cells  are  actively  dividing  while  the  leucocytes  are  not 
observed  to  be  doing  so.  It  would  seem  absurd  at  such  a  stage  to  talk 
of  the  derivation  of  red  cells  from  leucocytes,  and  if  this  is  the  case 
at  so  early  a  stage  of  development,  when  both  sets  of  cells  are  compara- 
tively undifferentiated,  it  would  seem  still  more  idle  to  suppose  that  in 
adult  life  there  can  be  relationship  between  the  two.  No  author  has 
attempted  to  connect  any  series  of  leucocytes  with  red  cells  other  than 
the  lymphocyte. 

One  fails,  indeed,  to  see  why  nucleated  reds  should  be  supposed  to  be 
formed  from  lymphocytes.  If  it  be  granted  that  erythroblasts  can  and 
do  multiply  by  mitosis,  which  nobody  doubts,  and  if  they  have  a  suit- 
able locus  for  development  as  they  have  in  the  bone-marrow,  there  is 
no  reason  whatever  to  suppose  that  their  activities  require  to  be  rein- 
forced by  the  lymphocytes  under  ordinary  conditions.  The  conditions 
in  lymphatic  leukaemia  alone  might  be  cited  as  a  sufficient  argument 
against  this  view.  We  have  gone  over  many  marrows  in  this  con- 
dition in  acute  cases  in  which  the  red  count  had  fallen  steadily  as  the 
white  count  rose.  These  marrows  had  undoubtedly  been  subjected  to 
a  functional  stimulus  and  were  full  of  large  lymphocytes,  but  we  had 
often  to  search  long  and  carefully  before  we  could  find  a  nucleated  red 
of  any  kind.  The  lymph  glands  in  these  cases  were  either  normal  or 
infiltrated  with  lymphocytes,  but  contained  no  nucleated  reds  outside 
the  blood-vessels.  Surely  in  these  cases  where  the  patients  were  dying 
of  anaemia,  if  in  any,  the  hypothetical  transformation  of  lymphocytes 
into  erythroblasts  ought  to  have  been  going  on.  But  we  could  never 
see  the  slightest  evidence  of  it;  indeed,  the  lymphocytes  were  often 
much  too  busily  employed  in  devouring  red  cells  to  have  any  time 
to  spare  for  the  making  of  them. 

The  Source  of  the  Lymphocytes  in  the  Blood. — We  have  been 
led  to  take  an  interest  in  this  from  the  experiments  which  we  have 
made  as  regards  digestion  leucocytosis.2     In  animals  we   found  that 

1  Bryce,  Trans.  Boy.  Soc.  Edin.,  1904. 

2  Goodall,  Gulland,  and  Paton,  Journ.  of  Physiol.,  xxx.  1903. 


110     DEVELOPMENT   OF   THE   CELLS   OF  THE   BLOOD 

the  rise  was  due  largely  to  an  increase  in  lymphocytes  which  was 
constant,  and  to  a  rise  also  in  the  polymorphs  which  was  not  so 
constant  but  might  reach  a  higher  figure.  We  succeeded  in  elimi- 
nating the  intestinal  mucous  membrane,  the  spleen  and  the  mesen- 
teric glands,  as  causes  of  this  increase,  and  Goodall  and  Paton x 
have  since  shown  that  the  source  of  these  lymphocytes  is  the 
bone-marrow.  Their  experiments  prove  that  the  actual  number  of 
lymphocytes  passing  into  the  blood  from  the  thoracic  duct  is  com- 
paratively small — much  smaller  than  one  would  have  expected;  and 
that  it  in  no  way  accounted  for  the  very  great  increase  of  lymphocytes 
in  the  blood.  On  the  other  hand,  the  blood  coming  from  the  marrow 
was  shown  to  be  very  much  richer  in  lymphocytes  and. in  polymorphs 
during  digestion. 

Many  other  observations  are  now  on  record  which  go  to  prove  that 
the  thoracic  duct  is  not  an  important  source  of  lymphocytes  in  the 
blood,  though  of  course  it  undoubtedly  does  carry  a  certain  number 
thither.  The  experiments  of  Crescenzi2  are  of  great  value  in  this 
respect.  After  splenectomy  and  drainage  of  the  thoracic  duct  it  was 
found  that  the  lymphocytes  dropped  rapidly  for  the  first  day  or  so,  as 
one  often  finds  to  be  the  case  after  an  operative  procedure  in  animals. 
But  after  one  to  four  days  the  lymphocytes  returned  to  the  normal 
point  or  rose  above  it.  Crescenzi  considers  that  this  is  due  to  a  direct 
passage  of  lymphocytes  into  the  blood  from  the  lymphatic  tissue, 
because  he  found  that  the  marrow  histologically  showed  no  compen- 
satory proliferation,  and  that  there  was  no  new  formation  of  collateral 
lymph  paths ;  but  it  seems  to  us  that  his  experiments  show  that  the 
marrow  was  in  reality  producing  lymphocytes  actively  all  the  time, 
and  of  course  no  compensatory  change  was  necessary. 

The  large  mononuclears  and  transitionals  showed  no  constant 
change  after  these  operations ;  they  were  sometimes  increased,  some- 
times diminished.  Our  own  experiments  on  the  function  of  the  spleen 
showed  pretty  definitely  that  that  organ  was  not  an  important  source 
of  lymphocytes,  and  the  experiments  of  Azzurini  and  Massart3  have 
confirmed  this. 

Further,  there  is  now  no  doubt  whatever  that  a  large  number  of 
lymphocytes  are  actually  present  in  the  marrow.  The  observations 
of  Pappenheim,  Price  Jones,4  Longcope,5  and  our  own  repeated  observa- 

1  Goodall  and  Paton,  Joum.  of  Physiol.,  xxxiii.  1905. 

2  Crescenzi,  Lo  liyvririuntale,,  1904. 

3  Azzurini  and  Massart,  Lo  Siierimentale,  1904 

4  Price  Jones,  Brit.  Med.  Joum.,  February  1905. 

5  Longcope,  Centralb.  f.  Bad.  u.  Paras.,  1904. 


I. 


n. 


§ 


HE 


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Os 


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TE 


CO  CO  b 

Plate  V. — H^ematogenesis. 


I.  Primitive  megaloblasts. 
11.  Non-haemoglobin-containing  erythroblasts  from  fcetal  liver. 

III.  a,  b,  Young  polyehromasic  megaloblasts  ;  c,  a  normoblast. 

IV.  a,  Primitive  leucocyte  developing  as  a  giant  cell. 

V.  Development  of  the  primitive  leucocyte  as  (a)  a   promyelocyte;  (b)  a  yoi 

(«)  an  older  myelocyte  ;  (d)  a  polymorphonuclear  neutrophil. 
VI.   Development  as  (a)  an  eosinophil  myelocyte  ;  (h)  an  eosinophil  polymorph. 
VII.   Development  as  («)  small  lymphocytes  ;  (b)  large  lymphocyte. 


A.  Q.,feoit. 


DEVELOPMENT   OE   THE   CELLS   OF   THE   BLOOD     111 

tions  have  put  this  beyond  doubt.  Longcope  found  in  the  marrow, 
under  normal  conditions,  22  to  23  per  cent.  Again,  there  are  certain 
diseases  where  there  is  a  marked  chemiotactic  passage  of  lymphocytes 
into  the  blood  from  the  marrow — in  whooping-cough  and  smallpox  in 
particular,  and  possibly  in  typhoid  also. 

Development  of  the  Eed  Cells 

(a)  In  Fatal  Life. — The  primitive  red  blood-cells  are  nucleated 
(megaloblasts)  (Plate  V.,  1).  They  are  first  produced  by  a  modifica- 
tion of  mesoblast  cells  in  the  vascular  area  surrounding  the  early 
embryo.  They  are  then  found  proliferating  in  the  foetal  vessels 
before  any  hemopoietic  organ  is  developed.  Great  numbers  show 
mitosis.  But  a  time  soon  comes  when  this  stock  is  insufficient  to 
maintain  the  necessary  supply  of  cells  and  at  the  same  time  carry 
on  respiratory  function.  As  soon  as  the  liver  is  developed  a  new  set 
of  cells  arises.  They  are  found  between  the  islands  of  liver  cells. 
These  are  erythroblasts  which  do  not  contain  hemoglobin.  The  absence 
of  hasmoglobin  is  to  be  accounted  for  by  the  fact  that  the  cells  are 
stationary  and  have  no  respiratory  function,  and  therefore  do  not 
require  it.  It  is  also  probable  that  haemoglobin  may  be  a  hindrance 
to  the  process  of  mitosis.  It  is  an  open  question  whether  these  cells 
are  derived  locally  from  undifferentiated  mesenchyme  cells  or  from  the 
circulating  haemoglobin-containing  megaloblasts. 

Bryce  discusses  this  question  in  connection  with,  the  spleen  in  his 
researches  on  lepidosiren,  and  concludes  for  the  former  alternative,  for 
the  reason  that  the  number  of  erythroblasts  is  out  of  proportion  to  the 
number  of  megaloblasts  showing  mitosis,  and  for  the  more  cogent  reason 
that  the  nucleus  of  the  erythroblast  differs  from  that  of  the  primitive 
megaloblast. 

The  question  is  difficult,  but  we  conclude  for  the  alternative  that 
the  erythroblasts  are  the  direct  progeny  of  the  first  megaloblasts.1 
We  can  distinguish  no  difference  in  nuclear  structure,  and  for  the 
reasons  just  indicated  there  can  be  little  doubt  that  the  erythroblasts 
can  and  do  proliferate  much  more  rapidly  than  the  first  megaloblasts. 
The  erythroblasts  having  arisen  may  proliferate  for  many  genera- 
tions without  haemoglobin,  or  may  begin  to  acquire  it  almost  at 
once.  Mitosis  may  occur  in  these  htemoglobin-containing  cells  (second 
megaloblasts),  which  are  indistinguishable  from  the  first  megaloblasts 
1  Goodall,  Journ.  of  Path,  and  Bad.,  1908. 


112    DEVELOPMENT   OF  THE   CELLS   OF  THE   BLOOD 

found  before  erythroblasts  are  developed.  This,  however,  is  uncommon 
as  compared  with  erythroblast  division. 

The  presence  of  megaloblasts  with  their  nuclei  undergoing  degenera- 
tion and  absorption  becomes  a  common  appearance,  and  even  at  a  fairly 
early  stage  in  foetal  life  the  great  majority  of  the  blood  corpuscles  in 
the  circulatory  system  are  non-nucleated.  The  proportion  of  nucleated 
cells  in  the  circulation  does  not  represent  the  activity  of  proliferation, 
and  their  presence  is  probably  not  so  much  due  to  the  proliferation  as 
to  the  disturbance  of  the  reticulum  of  the  hemopoietic  organs  which 
the  proliferation  causes. 

By  mid-term  many  of  the  nucleated  red  cells  have  a  nucleus  of  the 
normoblastic  type.  Thereafter  normoblastic  blood  formation  increases 
at  the  expense  of  the  megaloblastic,  with  the  result  that  in  course 
of  time  the  majority  of  the  circulating  red  corpuscles  are  normocytes 
and  not  megalocytes. 

Megaloblastic  blood  formation  persists  not  only  to  the  end  of  but 
for  some  time  after  foetal  life.  It  is  indeed  likely  that  it  never  entirely 
disappears.  It  does  not  follow  that  megalocytes  are  supplied  to  the 
circulation.  The  megaloblasts  give  rise  to  normoblasts ;  the  normo- 
blasts in  their  turn  give  rise  to  erythrocytes.  The  latter  process  con- 
sists in  the  internal  disintegration  and  absorption  of  the  nucleus.  The 
old  view  that  the  normoblasts  give  rise  to  erythrocytes  by  extrusion 
of  the  nucleus  is  now  almost  entirely  given  up.  A  normoblast  with  a 
partially  extruded  nucleus  may  occasionally  be  seen,  but  the  extrusion 
is  brought  about  in  the  process  of  manipulation. 

When  the  spleen  is  developed  it  takes  part  in  the  process  of 
hsematogenesis,  but  as  soon  as  the  marrow  is  formed  the  process  goes 
on  more  actively  there.  In  later  foetal  life  the  hemopoietic  activity 
of  the  liver  and  spleen  greatly  diminishes  and  terminates  altogether 
rather  abruptly  at  or  about  the  time  of  birth.  Meantime  the  marrow 
has  increased  greatly  in  amount,  and  becomes  the  only  source  of  the 
red  cells  supplied  to  the  organism. 

(b)  In  Post-Natal  Life. — The  source  of  the  red  corpuscles  is  the 
bone-marrow  only.  They  are  derived  from  normoblasts  which  pro- 
liferate in  response  to  the  needs  of  the  body.  The  nucleus  is  absorbed 
before  the  cells  escape  into  the  circulation.  In  pathological  conditions 
such  as  pernicious  anaemia  and  leukaemia  proliferation  of  red  cells  may 
again  take  place  in  the  liver  and  spleen  and  even  in  the  peripheral 
circulation. 

A  certain  number  of  cells  of  the  foetal  type  remain  in  the  boner 


DEVELOPMENT   OF   THE   CELLS   OF   THE   BLOOD     113 

marrow  in  later  life.  The  megaloblast  and  its  non-hsemoglobin-contain- 
ing  progenitor  remain  as  non-circulating  elements,  and  under  abnormal 
conditions  may  proliferate  to  such  an  extent  that  megalocytes  and 
megaloblasts  appear  in  the  circulating  blood.  In  the  same  way  the 
primitive  leucocyte  remains  a  normal  constituent  of  the  bone-marrow 
and  retains  its  potentialities  of  producing  all  the  members  of  the  white 
cell  group.  Under  ordinary  circumstances  it  is  probably  not  called 
upon,  any  more  than  the  surviving  megaloblasts  are  called  on.  The 
sequence  of  ordinary  development  goes  on  in  each  series  separately, 
but  in  such  extreme  pathological  disturbances  as  leucocythsemia  the 
primitive  leucocyte  may  play  a  very  important  part. 

The  following  scheme  summarises  the  genealogy  of  the  red  and 
white  cells : — 

MESENCHYME   CELL 


Mesenchyme 
cell 


Megaloblast 


Primitive  leucocyte 
(large  lymphoid  cell) 


Erythroblast 
without  Hb. 


Small  lym- 
phocyte 

Large  lym- 
phocyte 


Myeloblast        Megaloblast 


Large  Transi-  Basophil  Eosinophil 

mononuclear       tional       promyelocyte     promyelocyte 


Basophil 
myelocyte 

Basophil 
polymorph 


Eosinophil 
myelocyte 

Eosinophil 
polymorph 


Megalocyte 


Megalocyte 


Normo- 
blast 


Normo- 
blast 


Neutrophil 
promyelocyte  Erythrocyte 

Neutrophil 
myelocyte 

Neutrophil 
polymorph 

Literature. 

Frankel,  Folia  Hcematologica,  Archiv  xvii.   1913,  p.  1,  gives  a  historical 
resume  and  numerous  references. 


PAET    III 

DISEASES   OF  THE   BLOOD   AND   BONE-MABEOW 

CHAPTEE  XIV 

PEKNICIOUS   ANAEMIA 

Definition. — A  disease  characterised  by  severe  anaemia  of  megaloblastic 
type. 

Etiology. — Age. — The  disease  is  most  common  between  thirty  and 
fifty,  though  no  age  seems  exempt.  It  is  very  rare  in  children. 
Hutchison,  in  1904,  collected  eleven  cases  from  the  literature,  and 
of  these  only  five  appeared  to  him  to  be  genuine.  Cases  in  old  age 
are  much  more  common. 

Sex. — Curious  differences  exist  between  the  statistics  which  have 
been  published.  German  statistics  show  a  considerable  preponderance 
of  the  disease  among  females.  American  records,  on  the  other  hand, 
indicate  that  the  disease  is  more  common  in  males.  Our  experience  is 
in  accordance  with  the  latter.  Out  of  a  series  of  500  cases  which  we 
have  seen  171  were  females.  Social  conditions  have  no  influence.  The 
disease  is  common  among  the  well-to-do. 

Heredity  seems  sometimes  of  importance.  It  is  quite  common  to 
get  a  history  of  one  other  case  in  a  family.  In  one  of  our  cases  the 
patient's  father,  paternal  uncle,  brother  and  sister  had  all  died  of  the 
disease;  in  another  the  patient's  father,  uncle,  and  sister  had  died 
of  it. 

A  host  of  depressing  conditions  and  other  diseases  have  been 
suggested  as  causal  agents  in  pernicious  anremia,  and  in  individual 
cases  may  be  of  importance.  The  great  majority  of  these  are  at  least 
not  proven,  but  a  certain  proportion  of  cases  begin  during  pregnancy 
or  the  puerperium,  a  few  cases  have  followed  cancer  of  the  stomach, 
(though  secondary  antenna  is  infinitely  more  frequent),  and  cases  are- 
sometimes  due  to  bothriocephalus  infection.  We  have  noticed  a  rela- 
tively large  incidence  among  plumbers,  men   employed  in  gasworks,, 


PEENICIOUS   ANEMIA  115 

and  other  occupations  involving  the  breathing  of  impure  air.  Sewage 
gas  has  been  suggested  as  a  cause,  but  we  have  repeatedly  seen  cases 
in  which  the  patients  lived  in  isolated  houses  in  the  country,  where 
this  was  out  of  the  question.  Others  have  followed  syphilis  or  malaria. 
In  the  great  majority  of  cases  no  history  of  any  causal  factor  can  be 
ascertained,  and  dyspepsia,  usually  of  a  vague  and  ill-defined  character, 
is  the  only  condition  which  can  be  said  to  precede  it  with  any  constant 
frequency. 

Morbid  Anatomy  and  Histology. — The  pallor  of  the  body  in  a 
case  of  death  from  pernicious  anaemia  is  very  striking.  There  is 
generally  a  slight  icteric  tinge.  Post-mortem  lividity  is  very  slight, 
and  may  be  absent.  The  subcutaneous  fat  is  well  preserved.  There  is 
intense  anaemia  of  all  the  organs.  Haemorrhages  may  be  noted  in 
the  skin,  mucous  or  serous  membranes.  They  are  fairly  frequent 
in  the  meninges. 

The  Tongue. — Attention  has  been  directed  to  smooth,  atrophic- 
looking  areas  on  the  tongue  during  life  (Hunter).  We  have  been 
unable  to  find  any  microscopic  change  to  account  for  these  appear- 
ances, which  seem  to  be  due  to  a  physical  condition  of  the  superficial 
layers  of  the  epithelium. 

Stomach  and  Intestines. — A  great  variety  of  lesions  have  been  de- 
scribed. Among  these  are  atrophy  and  thinness  of  the  coats  of  the 
intestine,  smoothness  of  the  mucous  membrane  and  atrophy  of  glands,, 
and  overgrowth  of  lymphoid  tissue. 

Faber  and  Bloch  pointed  out  that  the  apparently  atrophic  changes 
were  in  large  measure  due  to  post-mortem  change,  and  stated  that 
they  were  not  found  if  the  abdomen  were  injected  with  formaline 
immediately  after  death. 

This  observation  we  have  been  able  abundantly  to  confirm.  In 
some  cases  there  is  certainly  some  degree  of  gastric  and  intestinal 
atrophy,  but  no  more  than  is  to  be  found  in  many  chronic  diseases. 
Haemorrhages  are  sometimes  seen  in  the  mucous  and  serous  coats. 
Occasional  ulcers  may  be  noticed  in  the  bowel,  but  with  no  special 
frequency.  In  the  submucosa  we  have  found  constantly  curious  baso- 
phil cells,  some  of  them  containing  enormously  large  granules  which 
may  greatly  distend  the  cell  and  whose  individual  size  may  be  greater 
than  that  of  a  red  blood  corpuscle. 

Liver. — The  liver  is  always  fatty.  There  is  always  a  considerable 
amount  of  pigmentation.     This,  for  the  most  part,  is  seen  towards  the 


116  PEKNTCIOUS   ANEMIA 

periphery  of  the  lobules.  This  pigment  has  a  golden  brown  colour, 
and  most  of  it  gives  the  free  iron  reaction.  Iron  is  seen  in  the  liver 
cells,  but  also  in  endothelial  cells  and  in  free  phagocytic  cells  in  the 
capillaries.  A  further  change  in  the  liver  is  the  presence  of  necrotic- 
looking  areas,  usually  in  the  middle  zone  of  the  lobules.  Between  the 
rows  of  necrotic  liver  cells  the  capillaries  are  widened,  and  in  the 
dilated  capillaries  are  numerous  nucleated  red  cells  (megaloblasts  and 
normoblasts)  and  phagocytic  cells  containing  red  corpuscles  or  pigment. 
The  latter  may  give  the  iron  reaction,  and  in  a  few  cases  so  completely 
that  the  whole  cell  becomes  blue  when  the  ferrocyanide  test  is  applied. 
Giant  cells  resembling  those  of  bone-marrow  are  to  be  seen  in  these 
areas  in  the  majority  of  cases. 

Spleen. — No  marked  or  constant  change  is  to  be  found  in  connection 
with  the  Malpighian  bodies.  The  pulp  shows  considerable  variation  as 
regards  the  kind  of  cell  preponderating.  In  most  cases  there  is  conges- 
tion, and  normoblasts  and  megaloblasts  in  varying  numbers  are  present. 
In  a  few  cases  lymphocytes  definitely  preponderate  in  the  pulp.  At 
least  half  the  cases  show  large  giant  cells  ingesting  red  corpuscles,  and 
sometimes  also  white  cells ;  giant  cells  resembling  those  of  bone-marrow 
are  sometimes  seen.  In  a  few  cases  there  are  numerous  basophil  cells 
in  the  pulp,  and  some  of  these  show  the  dropsical  appearance  seen  in 
those  of  the  intestine.  Pigment  is  present  in  varying  amount  in  all 
cases.  Usually  a  certain  proportion  of  this  gives  the  iron  reaction,  in 
some  cases  in  very  large  amount.  The  pigment  is  found  free  in  the 
pulp,  or  in  leucocytes  or  endothelial  cells. 

Kidneys. — In  nearly  every  case  there  is  catarrhal  or  interstitial 
nephritis,  the  former  probably  toxic  in  origin,  the  latter  probably  pre- 
existing, and  in  many  cases  granules  of  pigment  giving  the  iron  reaction 
are  seen  in  the  epithelium  of  the  convoluted  tubules,  sometimes  in  very 
large  amount.  This  iron  pigment  is  found  more  frequently  in  cases 
terminating  acutely  than  in  those  of  chronic  type. 

Heart. — In  the  great  majority  of  cases  the  heart  muscle  shows 
fatty  and  other  degenerative  changes,  though  not  in  an  extreme  degree. 
These  are  sometimes  absent.  In  typical  cases  of  fatty  degeneration  the 
familiar  "  thrush's  breast "  appearance  may  be  seen  on  the  endocardial 
surface  of  the  ventricles  in  particular. 

Lungs. — There  is  no  special  feature  associated  with  the  disease,  but 
patches  of  catarrhal  pneumonia  are  extremely  common,  and  many  cases 
terminate  with  croupous  pneumonia. 

Hcemolyrivph  Glands. — These  are  generally  numerous,  large,  and  dark 


PEENICIOUS   ANEMIA  117 

red  in  colour,  and  are  most  numerous  and  largest  immediately  in  front 
of  the  vertebral  column  in  the  lumbar  region,  especially  the  lower  part 
of  it.  They  show  very  great  hEemolytic  activity,  red  cells  being  in- 
gested by  large  phagocytes  in  great  numbers.  Pigmentary  changes  are 
not  so  marked  as  might  be  expected,  and  only  a  small  proportion  of  the 
pigment  present  gives  the  free  iron  reaction. 

The  Bone-Marrow. — The  bone-marrow  throughout  the  body  is  dark 
red  in  colour  and  increased  in  amount.  The  ordinary  fatty  marrow  has 
disappeared  and  there  is  a  very  considerable  absorption  of  bone,  so  that 
the  medullary  cavities  are  considerably  enlarged. 

The  striking  feature  of  sections  and  films  is  the  very  large  number 
of  megaloblasts  which  are  seen.  In  no  other  condition  are  they  so 
numerous  or  so  large.  Normoblastic  activity  is  also  very  great.  In 
some  cases  basophil  degeneration  of  the  red  corpuscles,  particularly  of 
the  nucleated  reds,  may  be  noticed,  but  it  is  not  nearly  so  frequent  as 
one  would  expect  from  its  incidence  in  the  circulating  blood. 

There  is  always  a  larger  proportion  of  white  cells  than  might  be 
expected  from  the  leucopenia  in  the  blood.  Considering  the  vast 
increase  in  the  amount  of  active  marrow  in  this  disease,  the  number 
of  marrow  leucocytes  must  be  very  greatly  in  excess  of  the  normal. 
In  view  of  this  it  is  difficult  to  explain  the  constant  leucopenia  and  the 
rarity  of  leucocytosis,  even  in  the  presence  of  severe  septic  complica- 
tions, unless  one  assumes  that  the  toxin  or  toxins  causing  the  disease 
in  some  way  interfere  with  the  passage  of  leucocytes  into  the  blood,, 
or  with  the  transformation  of  myelocytes  into  the  polymorphonuclear 
form.  It  is  to  be  noted  that  the  number  of  polymorphs  in  the  marrow 
is  always  small — much  smaller  than  in  a  normal  marrow.  In  nearly 
50  per  cent,  of  cases  white  cells  appear  more  numerous  than  the  red 
cells.  Those  present  are  mainly  myelocytes  or  lymphocytes.  They 
may  be  present  in  about  equal  proportions,  but  as  a  rule  one  or 
other  preponderates,  and  the  one  variety  preponderates  just  as  often 
as  the  other. 

Eosinophil  cells  are  seldom  numerous.  Basophils  are  present  in 
considerable  numbers  in  a  small  proportion  of  cases.  Giant  cells  are 
small  and  degenerated,  very  seldom  normal. 

There  is  generally  marked  evidence  of  blood  destruction,  as  shown 
by  phagocytosis  of  both  red  and  white  cells.  Pigment,  free  or  intra- 
cellular, showing  the  free  iron  reaction  is  found  in  about  one-third  of 
the  cases. 

The  Nervous  System. — Eecent  or  organised  haemorrhages  are  practi- 


118  PERNICIOUS  ANAEMIA 

cally  always  to  be  seen  in  the  membranes.  In  the  very  few  instances  in 
which  a  histological  examination  of  the  brain  has  been  made  there  have 
been  small  hemorrhages  in  the  brain  substance  and  some  indications 
of  impaired  nutrition  of  the  brain  cells. 

Observations  on  the  cord  have  been  more  numerous.  Small 
haemorrhages  are  usually  found.  The  vessels  are  often  dilated  and 
show  hyaline  degeneration.      There  are  small  foci  of  degeneration  in 

-v. 

the  white  matter  in  the  vicinity  of  vessels.  These  may  run  together 
to  form  large  areas  of  sclerosis,  and  may  thus  give  rise  to  secondary 
degeneration  of  the  nerve  tracts.  Combined  postero-lateral  sclerosis 
is  the  common  lesion.  Sclerosis  may  also  be  seen  in  the  gray  matter, 
though  it  is  not  so  common.  Nissl's  granules  may  stain  imperfectly, 
the  nucleoli  may  be  swollen,  and  the  protoplasm  of  the  cells  pigmented. 
The  lesions  are  more  common  in  the  upper  part  of  the  cord  than  the 
lower. 

The  peripheral  nerves  often  show  indications  of  neuritis. 

Relationship  of  Pathological  Appearances  to  Clinical  Features. — 
In  this  connection  we  find — 

1.  The  necrotic  areas  in  the  liver  are  more  marked  in  the  more 
chronic  cases. 

2.  The  more  acute  cases  show  more  iron  in  the  liver,  spleen,  and 
kidney,  and  in  the  more  chronic  cases  a  considerable  amount  of  pigment, 
which  does  not  give  the  iron  reaction,  is  present. 

3.  There  is  a  striking  relationship  between  the  acuteness  of  the  case 
and  the  number  of  megaloblasts  both  in  the  blood  and  in  the  marrow. 

4.  The  cases  which  have  shown  most  megaloblasts  in  the  blood 
show  most  megaloblasts  in  the  bone-marrow. 

5.  There  is  no  necessary  relationship  between  the  differential 
leucocyte  count  of  the  blood  and  the  marrow  type.  In  practically 
all  cases  the  blood  shows  leucopenia  with  a  relative  lymphocytosis. 

v  Pathology. — At  the  outset  we  may  state  that  the  fatty  and  other 
degenerative  changes  in  the  heart,  the  fatty  changes  in  the  liver,  the 
catarrhal  and  sometimes  also  the  interstitial  changes  in  the  kidney,  the 
fairly  frequent  patches  of  pneumonia,  and  the  nervous  lesions,  seem  to 
throw  no  light  on  the  pathology  of  the  disease,  but,  when  not  pre- 
existing, are  secondary  to  the  severe  anaemia  or  to  its  cause. 

Alimentary  Canal. — Much  diversity  of  opinion  exists  regarding  the 
importance  of  the  changes  found. 

We  are  inclined  to  think  that,  with  the  exception  of  the  presence  of 


Plate  VI. 


171. 


Fig.  I. — Aplastic  Red  Bone-Marrow. 

Blood-cells  are  .scanty.  Only  three  normoblasts  (-/()  and  two 
myelocytes  (m)  are  present.  The  section  shows  mainly  fat- 
cells  and  lymphocytes. 


Fig.  2.— Marrow  from  Case  of  Pernicious  Anemia. 

There  are  numerous  megaloblasts  (a),  some  showing  mitotic  figures. 

There  are  also  normoblasts  (ft). 
Myelocytes  (c)  are  numerous,  as  are  lymphocytes  (d).     There  are  a 

few  eosinophils. 
There  are  two  giant  cells,  one  young  (/)  with  basophil  protoplasm, 

another  older  with  acidophil  protoplasm  showing  an  ingested 

red  cell. 
Only  one  fat-cell  is  present  in  the  whole  field. 


A.  G.,  fecit. 


PEENICIOUS   ANAEMIA  119 

basophil  cells  as  described,  the  appearances  found  by  us  in  the  stomach 
and  intestine  could  be  summed  up  as  "  post-mortem  "  change. 

Liver. — The  large  amount  of  iron  in  pernicious  anaemia  is  a  striking 
feature.  Our  observations  lead  us  to  believe  that  this  accumulation  is 
due  to  two  factors — (a)  storage,  and  (b)  haemolysis. 

(a)  By  far  the  greater  part,  namely,  that  in  the  liver  cells  at  the 
portal  periphery,  is  simply  stored  up,  the  liver  being  the  normal 
channel  for  the  excretion  of  products  of  broken-down  haemoglobin. 
This  accumulation  is  greater  in  the  more  acute  cases,  because  the 
amount  of  iron  brought  to  the  liver  must  be  largely  in  excess  of  the 
usual  rate  of  elimination. 

We  do  not  look  upon  this  iron  as  indicative  of  anything  more  than 
mere  storage.  It  is  specially  marked  in  pernicious  anaemia,  because  of 
prolonged  accumulation,  but  it  is  not  pathognomonic,  and  we  have  seen 
more  iron  in  the  liver  in  cases  of  acute  lymphatic  leukaemia  than  in  the 
average  case  of  pernicious  anaemia. 

(&)  Altogether  apart  from  this  more  or  less  passive  storage,  we  find 
a  certain  amount  of  active  haemolysis  of  the  same  character  as  that 
seen  in  the  spleen,  haemolymph  glands,  and  marrow,  namely,  iron  con- 
tained in  endothelial  cells,  and  red  cells  and  pigment  contained  in 
large  phagocytes.  These  appearances  have  been  found  to  predominate 
over  the  passive  accumulation  in  the  liver  cells  in  animals  in  which 
sudden  blood  destruction  has  been  caused  by  the  injection  of  haemolytic 
agents. 

We  find  that  the  amount  of  iron  and  other  pigment  in  endothelial 
cells  in  the  liver  is  greater  in  the  acute  cases.  This  would  mean 
that  the  liver  in  acute  cases  is  obliged,  as  it  were,  to  deal  with 
large  quantities  of  the  first  products  of  the  disintegration  of  weakly 
or  weakened  red  corpuscles,  or  the  corpuscles  themselves,  while  in  the 
more  chronic  cases  these  products  are,  for  the  most  part,  brought  to  it 
in  a  state  more  suitable  for  storage.  The  passive  accumulation  of  iron 
frequently  obscures  the  more  active  haemolytic  process,  but  we  have 
seen  examples  of  the  usual  storage  at  the  periphery  of  lobules,  while 
towards  the  middle  and  central  part  of  the  lobule  there  was  haemolytic 
accumulation  of  iron  in  the  endothelial  cells.  It  is  not  unreasonable  to 
assume  that  the  megalocytes  of  pernicious  anaemia,  which  are  so  definitely 
foetal  in  their  characters,  are  ill  adapted  to  the  needs  of  adult  life,  and 
probably  have  a  shorter  existence  in  the  blood-stream  than  normal  red 
corpuscles. 

The  necrotic  areas  which  we  have  described  are  most  marked  in  the 


120  PERNICIOUS   ANiEMIA 

mid-zone  of  the  lobules,  and  are  usually  confined  to  that  situation.  In 
the  more  chronic  cases  they  extended  out  to  the  portal  zone. 

The  presence  of  a  considerable  number  of  red  cells,  often  nucleated, 
and  giant  cells  indistinguishable  from  those  of  bone-marrow,  is  sugges- 
tive that  in  some  cases  the  liver  may  revert  to  its  foetal  function  of 
blood  formation.  It  is,  of  course,  well  known  that  the  wide  capillaries 
in  the  foetal  liver  are  the  site  of  blood  formation  at  a  stage  of  develop- 
ment before  the  bone-marrow  is  formed.  These  capillaries  then  contain 
numbers  of  giant  cells,  nucleated  red  corpuscles,  and  leucocytes  of 
various  kinds.  The  fact  that  these  widened  capillaries  in  the  liver 
are  more  evident  in  chronic  cases  of  pernicious  anaemia  suggests 
that  in  them  the  whole  available  marrow  has  been  transformed  into 
erythroblastic  and  leucoblastic  tissue,  and  that  the  marrow  function 
has  overflowed  into  its  old  channels.  This  overflow  recalls  in  a  very 
striking  way  the  analogous  condition  of  deposits  in  the  liver  and 
elsewhere  in  long-standing  cases  of  leucocythaemia.  The  absence  or 
slighter  amount  of  the  change  in  the  acute  cases  may  be  taken  to 
mean  that  there  has  not  been  time  for  it  to  occur,  or  that  there  has 
not  been  a  sufficient  power  of  proliferation  in  the  marrow  to  permit 
of  its  occurrence. 

It  is  probable  that  the  necrotic  areas  are  due  to  pressure  and  inter- 
ference with  liver  function  from  the  accumulation  of  cells  possibly 
engaged  in  blood  formation,  and  cells  engaged  in  phagocytosis  in  the 
capillaries  between  them. 

On  the  other  hand,  it  might  be  that  the  necrotic  areas  are  due  to 
absorption  of  toxins  from  the  intestine,  but  against  this  view  is  the  fact 
that  they  are  more  marked  in  the  more  chronic  cases. 

The  fatty  changes  are  secondary  to  the  anaemia. 

Spleen. — We  now  know  that  the  spleen  does  not  play  any  very 
important  part  in  normal  haemopoietic  processes.  Its  main  function 
appears  to  be  the  removal  of  old  or  damaged  erythrocytes  from  the 
circulation,  and  we  have  no  reason  to  think  that  its  role  in  pernicious 
anaemia  is  different.  The  occasional  presence  of  basophil  cells  with 
large  dropsical  granules  might  suggest  some  localisation  of  toxin,  as  in 
the  case  of  the  intestine  and  bone-marrow. 

As  in  the  liver,  the  presence  of  bone-marrow-like  giant  cells  in  some 
cases  makes  it  seem  probable  that  in  prolonged  cases  the  spleen  attempts 
to  meet  the  demand  for  erythrocytes  by  returning  to  its  foetal  haemato- 
genic  function. 

Hcemolymph  Glands. — The  changes  simply  indicate  very  active  per- 


PERNICIOUS   A*LEMIA  121 

formance  of  the  normal  haemolytic  function,  chiefly  by  the  action  of 
large  phagocytes  derived  from  leucocytes  and  endothelium. 

Bone-Marrow. — In  every  case  the  naked-eye  change  is  identical,  and 
although  the  microscopic  picture  varies  according  to  the  kind  of  cell 
which  preponderates,  the  changes  are  essentially  the  same.  There  is 
undue  activity  of  reel  cell  and  white  cell  formation,  and  the  former 
assumes  the  megaloblastic  or  foetal  type.  The  hemolytic  changes  are 
similar  to  those  found  in  other  organs. 

All  our  observations  tend  to  convince  us  that  this  is  the  essential 
seat  of  the  disease.  If  the  bone-marrow  changes  be  secondary  and  some 
other  symptom-complex  be  primary,  would  it  not  be  reasonable  to  expect 
to  see  cases  clinically  before  the  bone-marrow  is  affected,  and  conse- 
quently before  megaloblasts  and  megalocytes  were  to  be  found  in  the 
blood  ?  And  if  we  exclude  the  blood  and  bone-marrow  changes  as 
essential  and  primary  features,  what  is  the  criterion  in  diagnosis,  and 
why  should  we  call  the  condition  pernicious  "  anaemia  "  ?  We  are  not 
in  agreement  with  those  observers  who  hold  that  the  marrow  changes 
are  secondary  phenomena. 

We  know  of  no  symptom-complex  apart  from  the  blood  changes 
or  of  any  morbid  appearance  apart  from  the  marrow  changes  which 
could  be  regarded  as  exclusively  distinctive  of  pernicious  anaemia. 

The  changes  are  due  to  exhaustion  of  the  bone-marrow,  or  inter- 
ference with  its  functions,  by  the  action  of  toxins.  It  is  not  necessary 
to  assume  that  these  toxins  are  in  all  cases  the  same. 

The  condition  can  be  caused  by  bothriocephalus  infection,  malaria, 
syphilis,  gastric  carcinoma,  and  probably  many  other  conditions,  and  the 
essential  features  are  due  rather  to  the  affection  of  a  definite  tissue — 
the  bone-marrow — by  varying  agencies,  than  to  an  affection  of  a  hetero- 
geneous group  of  organs  by  a  definite  toxin. 

Mere  loss  of  blood  is  not  sufficient  to  cause  pernicious  anaemia. 
After  severe  haemorrhage  the  marrow  becomes  red  in  a  few  days,  but 
the  nucleated  red  cells  found  in  the  marrow  and  blood  are  normoblasts, 
and  the  effects  of  haemorrhage  where,  presumably,  the  marrow  is  healthy 
are  readily  recovered  from.  We  have  never  seen  one  acute  or  chronic 
haemorrhagic  anaemia  develop  into  pernicious  anaemia.  Indeed  in  the 
histories  of  pernicious  cases  any  reference  to  haemorrhage  is  rare,  and  in 
our  experience,  even  in  the  fully-established  cases,  bleeding  is  not  nearly 
so  common  as  is  generally  supposed,  and,  apart  from  haemorrhage  into 
the  retina,  is  practically  confined  to  the  terminal  stages  and  to  the 
more  acute  cases. 


122  PERNICIOUS   ANAEMIA 

On  the  other  hand,  blood  destruction  by  such  agents  as  phenyl- 
hydrazin,  which  has  also  toxic  effects  on  the  bone-marrow,  is  followed 
by  megaloblastic  as  well  as  normoblastic  blood  formation. 

Eosenqvist x  has  made  an  important  study  of  metabolism  in  pernicious 
anaemia,  and  finds  that  there  is  a  toxic  increase  in  nitrogen  metabolism. 

The  toxaemia  is  paroxysmal,  owing  to  the  production  of  a  temporary 
relative  immunity  which  in  our  view  would  account  for  the  temporary 
improvements  seen  in  the  blood  condition,  indicating  corresponding 
improvement  in  the  bone-marrow. 

We  admit,  of  course,  that  haemolysis  may  precede  defective  haemato- 
genesis,  but  haemolysis  does  not  produce  the  various  phenomena  found 
in  pernicious  anaemia  until  the  bone-marrow  has  undergone  megalo- 
blastic degeneration.  The  essence  of  the  disease  is  not  mere  haemolysis 
or  poisoning  of  the  circulating  blood ;  it  is  a  toxic  affection  of  the  bone- 
marrow. 

Our  subsequent  experience  has  given  us  no  reason  to  alter  the 
views  regarding  the  nature  of  pernicious  anaemia  which  we  published 
in  1904.2 

1.  The  essential  feature  of  the  disease,  and  the  criterion  in  its 
diagnosis,  is  that  it  is  a  megaloblastic  anaemia. 

2.  The  widespread  evidences  of  blood  destruction  occurring  in  liver, 
spleen,  haemolymph  glands  and  marrow  indicate  abnormal  vulnerability 
in  the  blood-cells  rather  than  a  pathologically  excessive  haemolytic 
action  on  the  part  of  so  many  diverse  tissues. 

3.  The  accumulation  of  iron  in  the  liver  is  due  partly  to  the 
disintegration  of  weakened  or  weakly  blood  corpuscles  by  endothelial 
cells  and  leucocytes,  and  partly  (and  to  a  much  greater  extent)  to 
storage  of  iron,  which  is  the  product  of  red  blood  corpuscles  which 
have  been  disintegrated  by  phagocytes  or  toxins  elsewhere.  This 
accumulation  of  iron  in  the  liver  is  not  peculiar  to  pernicious  anaemia, 
and  is  the  natural  result  of  the  abnormal  amount  of  blood  destruction. 

4  There  is  no  direct  evidence  of  special  disease  of  the  intestine, 
and  the  intestine  need  not  be  the  primary  seat  of  toxin  production, 
though  in  certain  cases,  and  notably  in  bothriocephalus  anaemia,  it  is  so. 

5.  In  some  part  of  the  body  a  toxin  is  produced  which  acts  directly 
on  the  bone-marrow,  interfering  with  normoblastic  blood  formation, 
leading  to  megaloblastic  formation,  and  acting  with  negative  chemio- 
taxis  upon  leucocytes,  especially  of  the  neutrophil  variety. 

1  Zeitschr.  f.  Hin.  Med.,  Berlin,  xlix.  1903,  193. 

2  Journ.  of  Path,  and  Bad. 


PERNICIOUS   ANEMIA  123 

6.  The  large  red  blood  corpuscles  produced  by  such  a  marrow, 
perhaps  as  much  from  their  size  as  from  inherent  weakness,  fall  a 
ready  prey  to  endothelial  cells  and  leucocytes  in  the  "  hemolytic " 
organs,  notably  haemolymph  glands,  spleen,  and  marrow,  and  in  the 
more  acute  cases  the  liver  also. 

7.  It  is  quite  possible  that  certain  individuals  from  congenital  defect 
in  the  marrow  may  be  specially  prone  to  the  disease,  as  there  is  little 
doubt  that  the  megaloblastic  degeneration  represents  a  reversion  to  the 
foetal  type.  This  applies  specially  to  the  hereditary  or  family  type 
of  the  disease. 

Symptoms. — The  onset  of  the  disease  is  always  insidious.  It  is 
a  remarkable  fact  that  in  practically  all  large  collections  of  cases 
the  blood  count  has  been  about  1,200,000  when  the  patient  first 
came  under  observation. 


Fig.  23. — Schematic  Curves  to  Illustrate  the  Onset  and  Course  op  Acute 

and  Chronic  Cases. 

(Continuous  line,  acute  ;  broken  line,  chronic.) 

The  horizontal  lines  indicate  the  blood  count  in  millions  per  c.mm.  Note  the  insidious  onset  in  both 
types,  the  much  more  rapid  onset  of  relapses,  and  the  comparatively  brief  period  of  the  most  serious 
phases.    When  the  count  is  below  one  million,  patients  either  soon  die  or  have  an  early  remission. 

The  patient  practically  always  complains  of  muscular  weakness. 
While  this  is  the  almost  universal  complaint  that  causes  the  patient 
to  seek  medical  advice,  the  patient's  strength  in  relation  to  his  blood 
count  is  remarkable.  In  no  other  condition  of  anaemia  with  such  low 
blood  counts  could  patients  do  the  amount  of  work  that  is  sometimes 
done  by  sufferers  from  pernicious  ansemia. 

The  peculiar  lemon-yellow  pallor,  the  breathlessness,  the  feeble 
pulse  and  the  fever  in  a  typical  case  present  a  picture  which  could 
hardly  be  mistaken. 

On  the  other  hand,  a  patient  often  comes  complaining  of  weak- 
ness ;  the  pallor  may  not  be  noticeable  or  noticed,  other  symptoms 
are  vague  or  misleading  or  wanting,  and  the  disease  is  very  fre- 
quently overlooked,  Patients  almost  always  appear  well  nourished. 
There   is   no   loss  of   subcutaneous   fat,  and   there   is   often   a   slight 


124  PEENICIOUS   ANAEMIA 

generalised    oedema    which    helps    to    carry    out    the    suggestion    of 
plumpness. 

Alimentary  System. — There  is  almost  always  loss  of  appetite,  in 
some  cases  even  a  repugnance  for  food.  In  a  few  cases,  however, 
appetite  remains  good,  and  in  still  fewer  cases  it  is  excessive. 

Hunter's  suggestion  that  the  disease  is  due  to  carious  teeth  and 
filthy  mouths  may  be  dismissed  at  once.  We  have  seen  many  cases 
in  people  who  had  been  edentulous  for  many  years,  and  many  others 
in  people  with  mouths  that  had  been  well  cared  for.  Even  in  hos- 
pital patients  the  mouths  of  pernicious  anaemias  will  often  compare 
favourably  with  those  of  their  neighbours  suffering  from  other  dis- 
eases. In  some  cases  sensitiveness  and  soreness  of  the  tongue,  hard 
palate,  gums  and  cheeks  have  been  noticed.  Hyperaesthetic  points 
may  be  noted  and  seem  to  correspond  to  submucous  haemorrhages. 
Shallow  red  ulcers  of  the  tip  and  edge  of  the  tongue  are  sometimes 
seen,  and  may  serve  to  draw  attention  to  a  possible  blood  change.  We 
saw  recently  a  lady  whom  we  had  known  for  many  years,  who  was 
habitually  pale  as  the  result  of  a  cardiac  lesion,  and  whose  blood  on 
several  previous  occasions  had  been  found  to  be  normal.  She  com- 
plained of  a  sore  tongue  of  this  type,  and  was  found  to  have  3,600,000 
reds ;  haemoglobin,  82  per  cent. ;  colour  index,  1*1.  She  presented  at 
the  time  no  other  typical  symptoms,  and  recovered  for  a  time  under 
arsenic,  but  ultimately  died  in  a  second  attack.  These  small  ulcers 
may  precede  by  a  year  or  two  any  other  definite  symptoms,  but  where 
they  exist  we  have  always  found  that  the  blood  already  showed  the 
typical  change,  though  usually  only  in  a  minor  degree.  Diminution  in 
the  total  red  count,  a  colour  index  of  1  or  a  little  over  it,  slight  poikilo- 
cytosis,  occasional  polychromasia  or  basophilia,  and  a  low  leucocyte 
count  will  cause  pernicious  anaemia  to  be  suspected  in  these  cases. 

Pigmentation  of  the  buccal  mucous  membrane  has  been  noticed,  but 
is  rare. 

There  is  not  infrequently  a  sensation  of  pain  or  discomfort  in  the 
epigastrium. 

Attacks  of  vomiting  occur  in  some  cases  at  intervals,  and  are  occa- 
sionally prolonged  for  weeks.  No  food  at  all  may  be  retained,  and 
rectal  feeding  may  be  required. 

As  a  rule  hydrochloric  acid  is  absent  after  an  Ewald's  test-meal,  or 
greatly  diminished.  We  have  only  seen  three  cases,  in  which  this  point 
was  investigated,  in  which  the  total  acidity  and  proportion  of  free 
hydrochloric  acid  were  normal,  or  even  approached  the  normal.     Attacks 


PEKNICIOUS   ANAEMIA  125 

of  diarrhoea  occur  with  great  frequency,  and  are  often  associated  with 
the  attacks  of  sickness.  Diarrhoea  may  be  the  main  symptom,  and  we 
have  seen  cases  in  which  the  diagnosis  of  tubercular  and  malignant 
ulceration  of  the  bowel,  sprue,  mucous  colitis,  etc.,  had  been  made  before 
the  blood  was  examined.  The  liver  is  not  usually  enlarged  in  acute  or 
early  cases.  In  chronic  cases  enlargement  is  not  uncommon,  but  is 
seldom  very  great  in  amount.  We  have  seen  enlargement  of  the  liver 
come  and  go  with  successive  attacks  and  remissions. 

The  character  of  the  faeces  varies  greatly.  They  may  be  quite 
normal  to  the  naked  eye  and  on  microscopic  examination,  but  in  cases 
with  gastro-intestinal  symptoms  may  be  of  peculiar  chrome  colour,  not 
unlike  that  of  new  brown  boots,  and  may  contain  a  good  deal  of  mucus. 
In  other  cases  of  this  type  a  fair  amount  of  blood  may  be  found  by  the 
benzidine  and  other  reactions,  or  the  stools  may  be  pale  and  coated  with 
mucus  or  muco-pus.     Hemorrhages  from  the  bowel  may  occur. 

Hemopoietic  System. — The  spleen  is  always  firm  in  consistency ;  its 
size  is  variable.  In  the  great  majority  of  cases  it  is  not  enlarged,  but  in 
a  fair  number  of  cases  it  may  be  slightly  enlarged,  and  in  a  still  smaller 
number  of  cases  its  enlargement  may  be  considerable,  but  its  lower 
border  is  very  seldom  more  than  about  an  inch  below  the  costal  margin. 
It  follows  the  same  rule  as  the  liver  as  regards  the  time  in  the  disease 
when  enlargement  is  found.  Cases  with  marked  enlargement  of  liver 
and  spleen  have  always  lasted  for  a  considerable  time,  and  the  prognosis 
is  relatively  though  not  absolutely  bad. 

The  lymphatic  glands  are  not  demonstrably  affected.  The  other 
ductless  glands  show  no  change. 

Circulation. —  Palpitation  is  frequently  a  distressing  symptom. 
Dyspnoea  is  brought  on  by  slight  exertion.  Faintness  is  not  so 
frequently  complained  of,  but  we  have  seen  cases  in  which  there 
were  repeated  syncopal  attacks.  These  may  even  be  fatal.  In  severe 
cases  the  heart's  action  is  excited ;  in  other  cases  it  may  be  difficult  to 
localise  the  cardiac  impulse  either  by  inspection  or  palpation.  The  area 
of  cardiac  dulness  is  not  usually  abnormal,  unless  strain  has  produced 
dilatation,  or  there  be  some  pre-existing  cardiac  lesion.  A  soft  blowing 
systolic  murmur  can  usually  be  heard  over  the  different  orifices  in  bad 
cases ;  in  milder  degrees  murmurs  may  only  be  heard  at  certain  areas, 
may  be  present  intermittently  or  only  after  exercise,  or  not  at  all. 
They  are  much  less  frequently  heard  in  elderly  patients.  Diastolic 
murmurs  are  rarely  heard.  Murmurs  over  the  jugular  veins  are  present 
in  severe  cases.     The  pulse  is  always  increased  in  frequency.      It  is 


126  PERNICIOUS  ANEMIA 

generally  over  80,  even  during  remissions.  With  slight  exercise  it 
increases  to  110  or  120.  It  is  of  small  volume  and  low  pressure,  and 
the  arterial  wall  is  not  specially  thickened.  Irregularity  is  seldom 
noticed  unless  there  be  some  pre-existing  cardiac  condition  with  which 
this  is  associated. 

Respiratory  System. — There  is  little  to  note  in  the  absence  of  com- 
plications. Many  patients  have  a  slight  and  sometimes  an  irritating 
persistent  cough. 

Integumentary  System. — The  pallor  of  the  skin  in  a  typical  case  is 
striking ;  it  has  a  peculiar  waxy  lemon-yellow  tint,  which  is  practically 
diagnostic.  This  tint  is,  however,  not  always  present,  and  it  must  be 
remembered  that  patients  with  a  fairly  high  count  of  red  cells  may  not 
show  any  noticeable  pallor.  For  example,  a  patient  with  a  count  of 
3,000,000  reds,  and  haemoglobin  80  per  cent.,  will  have  a  practically 
normal  complexion.  The  mere  count  may  bear  little  relation  to  the 
pallor.  For  example,  we  saw  a  patient  recently  with  a  red  count  of 
2,300,000,  haemoglobin  60  per  cent.,  who  showed  the  lemon-yellow  tint 
remarkably  well.  At  this  time  she  was  suffering  from  gastro-intestinal 
symptoms,  with  high  fever.  A  month  later  these  symptoms  had 
disappeared  under  treatment,  and  though  her  red  count  and  haemo- 
globin were  practically  the  same,  her  complexion  was  of  good  colour, 
with  only  very  slight  pallor.  The  toxaemia  in  acute  cases,  or  cases  with 
acute  symptoms,  has  as  much  to  do  with  the  complexion  as  the  anaemia. 
There  is  sometimes  an  ordinary  untinted  pallor,  but  there  is  seldom  the 
deathly  whiteness  which  is  seen  in  chronic  Bright's  disease,  or  post- 
hemorrhagic anaemia.  Some  patients  have  a  somewhat  brownish 
colouration,  which  is  apt  to  obscure  the  real  pallor,  while  weather- 
beaten  faces  may  not  suggest  anaemia  at  all. 

A  quite  definite  icterus  is  seen  in  the  skin  and  conjunctivae,  in  a 
small  proportion  of  cases.  The  lemon-yellow  tint  is  due  to  a  slight 
toxaemic  jaundice  in  addition  to  pallor,  and  is  only  seen  in  cases  which 
are  not  doing  well  or  where  toxic  symptoms  are  marked. 

Pigmentation  resembling  that  of  Addison's  disease  is  not  uncommon. 
It  is  more  frequent  in  people  who  have  taken  much  arsenic,  but  occurs 
also  in  untreated  cases  seen  for  the  first  time,  and  may  confuse  diagnosis. 
As  regards  position  and  character,  it  may  exactly  simulate  the  pig- 
mentation of  Addison's  disease,  or  may  be  less  typical.  It  is  almost 
always  most  marked  on  the  abdomen. 

A  slight  persistent  oedema  of  the  lower  eyelid  and  ankles  is  a 
common  symptom,  and  the  oedema  may  be  more  general. 


PERNICIOUS   ANAEMIA  127 

Small  petechial  haemorrhages  are  fairly  common.  Larger  haemor- 
rhages are  rare.  Petechiae  may  be  seen  in  the  mucous  membrane  of 
the  mouth.  Haemorrhages  are  much  more  common  from  mucous 
membrane  than  from  the  skin. 

The  skin  is  dry,  but  slight  exertion  or  excitement  easily  lead  to 
profuse  perspirations. 

Genito- Urinary  System. — The  urine  in  all  ordinary  respects  shows 
little  abnormality.     The  specific  gravity  is  usually  low. 

A  marked  "indican"  reaction  is  usually  obtained,  and  a  colour 
reaction  on  the  addition  of  nitric  acid  is  common.  These  may  be  taken 
as  evidence  of  absorption  of  products  of  putrefaction  from  the  bowel  and 
thus  give  useful  indications  for  treatment. 

Considerable  importance  has  been  attached  to  the  occurrence  in  the 
urine  of  urobilin,  but  the  probability  is  that  urobilinuria  is  more  or  less 
an  accidental  occurrence  at  any  time,  and  might  happen  in  health  just 
about  as  readily  as  in  pernicious  anaemia. 

A  transient  albuminuria  is  not  uncommon  during  the  acuter  stages 
of  the  disease,  and  association  with  acute,  or  more  usually  chronic, 
Bright's  disease  is  not  very  rare.  In  our  post-mortems  we  have  been 
struck  by  the  fact  that  the  kidneys  are  practically  never  normal,  and  it 
is  probable  that  the  stupor  and  coma  which  often  occur  in  the  terminal 
stages  are  at  least  partly  due  to  chronic  uraemia.  Many  of  these  cases 
die  with  a  relatively  high  red  count,  often  over  a  million,  while  some  of 
the  cases  with  counts  of  400,000  or  so  remain  clear  mentally  until  just 
before  the  end.  "We  have  seen  cases  terminate  by  ordinary  acute 
uraemia,  with  convulsions,  and  sometimes  complete  suppression  of  urine. 
In  the  most  marked  of  these  last  cases  the  patient  was  pregnant,  and 
the  suppression  occurred  as  the  result  of  premature  labour. 

Rosenqvist  found  a  periodic  increase  of  nitrogen.  The  output  of 
phosphates  is  increased. 

Menstruation  nearly  always  ceases  in  established  cases,  but  may 
return  during  remissions.  "We  have  recently  met  with  several  excep- 
tions to  this  rule,  all  in  women  approaching  the  menopause.  In  two 
cases  fibroid  tumours  of  the  uterus  were  found  to  be  present.  We  were 
struck  with  the  comparatively  small  lowering  of  the  red  cell  count — or 
absence  of  change — in  those  cases  as  the  result  of  what  was  sometimes 
pretty  severe  bleeding. 

Nervous  System. — There  are  nervous  symptoms  of  some  sort  in  about 
30  per  cent,  of  cases.  In  most  instances  these  are  subjective  sensations 
of  tingling  or  numbness  in  the  feet  and  legs,  more  rarely  or  in  less 


128  PERNICIOUS  ANEMIA 

decree  in  hands  and  arms.  There  is  sometimes  diminished  sensibility 
and  weakness,  and  less  frequently  there  is  actual  neuritis.  It  is  often 
difficult  to  determine  to  what  extent  this  may  be  due  to  arsenic. 

Cord  symptoms  sometimes  occur.  They  are  often  indefinite,  and  as 
a  rule  are  less  than  the  lesions  found  after  death  might  have  been  expected 
to  occasion.     The  deep  reflexes  are  frequently  diminished  or  lost. 

Symptoms  of  degeneration  of  the  posterior  columns,  or  of  both 
posterior  and  lateral  columns,  are  the  most  definite  of  all  the  nerve 
symptoms.  These  may  go  the  length  of  marked  ataxia,  and  may 
closely  simulate  tabes  dorsalis.  Spastic  symptoms  are  much  less 
common.  The  severity  of  the  cord  symptoms  bears  no  necessary 
relation  to  the  ansemia,  and  when  once  established  they  tend  to  be 
slowly  progressive  as  a  rule,  though  they  may  remain  stationary. 
They  usually  begin  during  a  period  of  ansemia,  but  not  invariably,  and 
persist  even  though  the  patient  is  otherwise  well.  We  have  seen  a 
patient  who  was  completely  bedridden  by  his  ataxia  whose  blood  count 
was  quite  normal,  though  the  film  showed  the  changes  we  describe  as 
occurring  during  remissions.  He  had  a  history,  however,  of  two 
undoubted  and  severe  attacks  of  pernicious  anaemia  some  years  pre- 
viously. Sometimes  the  nerve  symptoms  are  complained  of  before  the 
symptoms  of  anaemia,  and  one  may  show  exacerbations  or  amelioration 
without  the  other  being  affected.  We  have  seen  one  case  in  which  the 
cord  symptoms  began  as  spastic  paraplegia  with  some  rigidity,  increased 
knee-jerks,  clonuses  and  extensor  response.  Sensory  symptoms,  with 
the  exception  of  tingling  in  legs,  feet,  and  hands  were  absent.  A  few 
months  later  the  signs  of  increased  muscle  tone  had  passed  off,  the  knee- 
jerks  could  hardly  be  elicited,  there  was  no  plantar  reflex  of  any  kind, 
and  there  was  definite  loss  of  sensation  in  both  legs.  The  ansemia  in 
this  case  was  of  chronic  type,  and  showed  very  little  change  throughout. 
The  probability  is  that  the  degeneration  does  not  depend  on  the  ansemia 
so  much  as  on  a  toxin  which  is  the  cause  of  both. 

Mental  Symptoms. — Patients,  as  a  rule,  do  not  exhibit  that  irritability 
of  temper  which  is  sometimes  seen  in  other  severe  anaemias.  On  the 
contrary,  there  is  commonly  a  great  complacency,  both  as  regards 
surroundings  and  as  regards  the  gravity  of  the  disease.  Exceptions 
are,  of  course,  met  with,  and  the  intelligent  patient  who  takes  too  keen 
an  interest  in  his  temperature  and  the  number  of  his  red  corpuscles 
may  provide  himself  with  a  good  deal  of  worry  and  his  medical 
attendant  with  opportunity  for  the  exercise  of  a  considerable  amount 
of  tact. 


PEENICIOUS   ANAEMIA  129 

Neurasthenia  is  not  an  uncommon  symptom,  and  we  have  seen  one 
case  in  which  neurasthenia  existed  for  years  before  the  blood  changes 
were  present.  The  converse  is,  of  course,  much  more  frequent,  and 
many  an  unfortunate  patient  with  pernicious  anaemia  is  labelled  neur- 
asthenia simply  because  the  blood  has  not  been  examined. 

Sleeplessness  is  often  a  distressing  symptom.  It  sometimes,  but  by 
no  means  always,  depends  on  gastro-intestinal  disturbance,  and  disappears 
when  this  is  successfully  treated. 

Actual  mental  symptoms  are  sometimes  seen.  Maniacal  attacks, 
hallucinations,  and  delirium  may  occur,  usually  towards  the  end  of  the 
disease.  In  a  small  proportion  of  cases  mental  symptoms  are  very 
prominent.  In  one  of  our  cases  there  was  a  history  of  an  attack  of 
anaemia  twelve  years  before,  followed  by  insanity,  which  necessitated 
detention  in  an  asylum  for  nearly  a  year.  She  remained  well  for 
eleven  years,  and  came  into  our  hands  with  a  second  attack  of  perni- 
cious anaemia.  In  the  course  of  this  she  again  became  insane,  and  died 
suddenly  while  the  arrangements  for  her  removal  to  an  asylum  were 
being  made.  A  fairly  constant  feature  of  the  insanity  of  pernicious 
anaemias  is  its  association  with  delusions  of  suspicion  and  persecution, 
and  unfortunately  it  is  usually  near  relatives  who  are  suspected  by 
patients.  We  have  seen  very  distressing  cases  where  husbands,  wives, 
and  favourite  children  were  execrated  by  their  spouses  or  parents.  As 
with  the  cord  symptoms,  the  mental  symptoms  may  bear  no  relation  to 
the  anaemia.  In  one  remarkable  case  a  patient  became  insane  without 
obvious  anaemia,  improved,  and  at  last  recovered  mentally  as  pernicious 
anaemia  became  progressively  severer,  and  again  relapsed  mentally  as 
his  blood  returned  to  the  normal. 

Speech  is  sometimes  slow  and  slurring,  but  often  suggests  that  the 
patient  will  not  take  the  trouble  to  articulate  his  words. 

Special  Senses. — Eye  symptoms  are  common ;  subjective  symptoms 
are  sometimes  complained  of.  There  may  be  dimness  of  vision  or 
flashes  of  light,  there  may  be  oedema  of  the  lower  eyelid,  and  there 
is  sometimes  haemorrhage  into  the  conjunctivae. 

Betinal  haemorrhages  are  common.  The  optic  disc  is  very  pale,  so 
that  the  haemorrhages  show  up  with  great  distinctness.  They  may 
be  small  and  punctate,  or  may  occupy  the  whole  disc.  In  one  case  a 
patient  complaining  of  dimness  of  vision  was  found  to  have  a  double 
central  scotoma,  without  change  in  the  discs.  His  reds  were  3,200,000, 
his  haemoglobin  80,  the  film  very  characteristic,  but  he  did  not  look  pale. 
He  died  of  pneumonia  about  a  fortnight  after  coming  under  observation. 

9 


130  PERNICIOUS   ANEMIA 

Tinnitus  is  a  common  symptom.  Deafness  is  rare,  but  may  become 
very  marked.  It  may  be  due,  in  some  cases,  to  haemorrhage  into  the 
inner  ear,  but  this  has  not  been  demonstrated  so  definitely  as  in  leukaemia. 

Eichhorst  has  noted  loss  of  smell  and  taste,  and  we  have  seen  one 
case  in  which  both  senses  were  practically  lost  without  local  defect. 
Improvement  in  the  anaemia  was  accompanied  by  improvement  in  both 
senses,  but  complete  recovery  did  not  occur. 

Locomotor  System. — The  muscles  are  soft  and  flabby.  Pain  over  the 
long  bones  is  often  present,  and  may  be  associated  with  tenderness. 
The  pain  is  seldom  mentioned  without  a  leading  question. 

Temperature. — Fever  is  present  at  some  time  in  about  two-thirds  of 
the  cases;  it  is  most  uncertain  in  its  incidence  and  duration.  The 
temperature  may  be  normal  or  subnormal  for  weeks  or  months  and  then 
it  rises  to  101°  or  102°,  and  with  a  daily  variation  of  about  a  degree 
remains  high  for  weeks  and  then  may  as  unaccountably  subside.  The 
fever  is  most  commonly  seen  in  acute  cases,  but  apart  from  that  observa- 
tion it  appears  to  bear  little  relation  to  the  severity  of  the  disease  or 
to  the  blood  changes.  It  is  sometimes  accounted  for  by  intestinal, 
pulmonary,  or  septic  complications,  but  often  occurs  without  any  cause 
which  either  ante-  or  post-mortem  evidence  reveals,  and  seems  not 
infrequently  to  be  due  to  the  inability  of  the  already  overworked  liver 
to  deal  with  toxins. 

The  Blood  Changes. — When  a  case  comes  under  observation  for 
either  anaemic  or  gastro-intestinal  symptoms  the  changes  in  the  blood 
are  usually  already  well  marked  and  definite.  An  average  estimation 
would  be  reds,  1,500,000 ;  haemoglobin,  40  per  cent. ;  colour  index,  there- 
fore, 1*3  ;  whites,  4000.  These  figures  are,  of  course,  subject  to  wide 
variations,  for  patients  vary  greatly  in  their  sensitiveness  to  anaemia. 
Sometimes  the  figures  are  much  higher  —  with  a  count  of  from 
2,500,000  to  3,000,000  reds ;  sometimes  the  count  will  have  dropped 
to  1,000,000.  One  reason  for  this  difference  is  probably  the  rate  at 
which  the  blood  deterioration  has  progressed.  If  it  has  been  gradual 
the  lower  figures  are  more  likely  to  be  reached;  if  it  is  rapid  the 
upper  are  more  likely  to  be  observed.  With  a  slow  blood  change  the 
organs  become  accustomed  to  the  anaemia ;  with  a  rapid  fall  in  corpuscles 
diminished  oxygenation  is  felt  more  quickly.  The  colour  index  also 
varies  considerably  at  this  stage.  The  more  chronic  the  case  the  more 
likely  is  it  to  be  1*0  or  just  above  TO,  while  in  the  acuter  and  more 
severe  cases  it  may  reach  1*5,  and  in  isolated  cases  may  go  even  higher. 


PERNICIOUS  ANEMIA  131 

The  average  is  1*2  or  1*3.  The  raised  colour  index  is  the  most 
important  single  point  in  the  diagnosis  of  pernicious  anaemia.  No 
other  of  the  ordinary  anaemias  ever  show  a  colour  index  above  1*0, 
although  indices  of  09  may  be  reached  by  very  severe  secondary 
anaemias  of  hemorrhagic  or  septic  type.  The  only  condition  of 
importance  in  which  the  colour  index  may  sometimes  be  above  1*0 
is  acute  lymphatic  leukaemia,  and  in  that  case  the  blood  changes  in 
other  directions  are  sufficiently  characteristic  to  make  the  diagnosis 
easy.  The  cause  of  this  raising  of  the  colour  index  has  been  con- 
siderably debated.  Some  authors  have  gone  the  length  of  assuming 
that  haemoglobin  must  be  present,  dissolved  in  the  serum,  in  order  to 
produce  it.  But  hemoglobinuria  is  of  very  rare  occurrence  in  per- 
nicious anaemia,  and  it  would  of  necessity  be  much  more  frequent  were 
haemoglobin  to  be  anything  like  so  constantly  present  in  the  serum  as 
the  constancy  of  the  raised  index  would  demand.  The  more  reasonable 
explanation  is  that  the  red  corpuscles  on  the  average  contain  each  a 
greater  quantity  of  haemoglobin  than  they  should  do,  and  that  this  is 
the  reason  is  borne  out  by  the  facts  that  so  many  of  the  red  corpuscles 
are  larger  than  normal  when  examined  in  films,  and  also  that  it  is  often 
possible  to  diagnose  pernicious  anaemia  when  one  is  counting  the  red 
cells  diluted  with  Hayem's  solution,  because  of  their  deeper  colour  and 
larger  size  in  the  counting  chamber. 

The  leucocytes  are  almost  invariably  diminished,  the  average 
number  being  somewhere  about  4000,  although  in  early  favourable 
cases  6000  or-  7000  may  be  found.  Leucocytosis  is  exceedingly  rare, 
and  very  seldom  attains  a  high  figure.  The  ordinary  influences  which 
produce  this  change  do  not  appear  to  act  in  pernicious  anaemia.  For 
example,  we  have,  on  several  occasions,  seen  a  patient  pass  through, 
and  recover  from,  an  attack  of  pneumonia  without  the  leucocytes  being 
altered  in  any  way,  and  on  many  occasions  we  have  seen  terminal  septic 
conditions  fail  to  raise  the  count.  On  eight  occasions  we  have  noted 
a  leucocytosis.  In  six  of  these  it  did  not  rise  above  15,000.  In  five 
of  the  cases  there  was  albumin  in  the  urine ;  in  two,  counts  of  10,000 
and  12,000  remained  unexplained,  and  were  quite  temporary.  In  the 
last  case  there  was  a  leucocytosis  of  56,400.  Eeds  were  2,470,000 ; 
haemoglobin,  65;  colour  index,  lm3,  with  a  very  typical  film.  The  urine 
contained  albumin,  and  there  was  an  acute  left-sided  pleurisy  and  peri- 
carditis, with  high  temperature.  The  urine  was  suppressed  soon  after 
the  patient  was  seen,  and  she  died  two  days  later.  We  have  been 
specially  struck  by  the  association  of  kidney  mischief  with  leucocytosis 


132  PEENICIOUS  ANAEMIA 

in  this  disease,  but  there  may  be  definite  chronic  B right's  disease  with  a 
subnormal  white  cell  count.  On  the  other  hand,  there  may  be  extreme 
leukopenia.  A  recent  instance  will  illustrate  this.  A  lady  of  70, 
who  had  been  anaemic  for  about  a  year,  suddenly  developed  a  tempera- 
ture of  103°,  with  a  rigor  and  retention  of  urine.  The  physical  signs 
when  she  was  seen  immediately  after  were  not  definite,  but  a  pneumonia 
developed,  and  she  died  two  days  later.  The  count  was — red  cells, 
1,570,000;  hsemogoblin,  38;  colour  index,  1-2;  whites,  1000.  The  film 
was  typical  as  far  as  the  red  corpuscles  were  concerned,  but  all  the 
white  cells  appeared  to  be  lymphocytes,  both  in  the  counting  chamber 
and  in  the  films.  This  would  naturally  make  one  think  of  an  acute 
lymphatic  leukaemia,  but  the  long  history  of  anaemia,  the  characters  of 
the  blood  in  other  respects,  the  absence  of  enlargement  of  liver,  spleen, 
or  lymph  glands,  made  one  consider  that  one  was  dealing  with  a  very 
severe  infection  which  was  excluding  from  the  blood  the  probably  small 
number  of  polymorphs  previously  present.  The  subsequent  develop- 
ment of  a  fatal  pneumonia  confirmed  this  view.  Such  cases  are  rare, 
however. 

Examination  of  Film  Preparations. — In  making  films  the  observer 
will  generally  notice  that  the  blood  spreads  out  much  more  easily  than 
usual,  and  this  is,  of  course,  more  marked  the  more  anaemic  the  blood. 
Often  when  the  blood  is  drawn  it  does  not  look  homogeneous,  but  the 
corpuscles  tend  to  separate  themselves  almost  at  once  from  the  plasma, 
so  that  it  looks  like  a  badly-made  emulsion  of  red  particles  in  a  pale 
yellow  fluid. 

The  Red  Corpuscles. — When  compared  with  normal  blood  it  will  be 
seen  at  once  that  the  average  size  of  the  corpuscles  is  larger  in  this 
disease,  and  if  a  film  of  normal  blood  and  one  of  pernicious  anaemia 
be  stained  at  the  same  time  and  in  exactly  the  same  way,  the  corpuscles 
in  the  latter  will  be  found  to  have  taken  on  more  of  the  stain.  This 
statement,  however,  applies  only  to  the  average,  for  there  are  great 
variations  in  different  cases  in  the  actual  appearance  of  the  corpuscles. 
Sometimes  they  are  almost  all  equal  or  nearly  equal  in  size,  sometimes 
very  large  ones  are  found  side  by  side  with  very  small  ones,  and  the 
small  ones  may  be  so  numerous  as  to  bring  down  the  colour  index 
to  unity.  A  recent  case  examined  by  a  very  competent  observer  nine 
months  before  we  saw  her  had  a  colour  index  of  T15  with  all  the  red 
corpuscles  large.  Two  estimations  by  ourselves  at  a  fortnight's  interval 
gave  an  index  of  just  over  1  on  both  occasions.  The  large  and  small 
cells  were  about  equal  in  numbers.     Poikilocytosis  may  be  very  marked 


PEENTCIOUS   ANEMIA  133 

or  may  be  almost  entirely  absent,  and  the  alteration  in  the  shape  of  the 
corpuscles  does  not  seem  necessarily  to  be  connected  with  any  difference 
in  the  clinical  course  of  the  disease,  although,  as  a  rule,  the  chronic 
cases  are  those  which  show  least  poikilocytosis,  the  acute  ones  those 
which  show  most.  As  a  rule  the  corpuscles  in  the  former  case  show 
a  rounded  outline,  but  in  certain  cases  large  numbers  of  them  are  more 
or  less  elongated  or  oval.  It  depends  very  much  on  the  spreading 
of  the  film  whether  the  central  concavity  is  well  seen  or  not.  In  the 
thinner  parts  it  is  apt  to  disappear,  while  if  a  thick  film  be  examined  it 


Fig.  24. — Photograph  of  Blood-film  from  Case  of  Pernicious  Anemia 
showing  a  megaloblast  in  mltosis. 

Eosine  and  methylene  blue,     x  1000. 

can  often  be  found  to  be  still  present,  and  to  have  round  it  a  much 
thicker,  plumper  rim  of  cell  plasm  than  the  normal  corpuscle.  A  con- 
siderable proportion  of  the  corpuscles  are  often  found  to  show  the  cup 
shape.  Polychromasia  is  very  common.  As  a  rule  the  large  corpuscles 
or  megalocytes  are  most  liable  to  show  it,  but  sometimes  one  finds  the 
change  pretty  evenly  distributed  throughout  the  film,  and  again,  if 
normal  blood  be  stained  along  with  a  film  from  a  case  of  pernicious 
anaemia,  the  red  corpuscles  in  the  latter  may  sometimes  all  exhibit 
a  bluish  tone  as  compared  with  the  colour  of  the  normal  corpuscles. 
Granular  degeneration,  or  basophilia,  is  seen  more  frequently  in  this 
disease  than  in  any  other,  but  varies  very  strikingly  in  its  incidence 
in  individual  cases.     Whole  films  taken  from  chronic  cases  may  be  gone 


134  PEENICIOUS  ANAEMIA 

through  without  a  single  example  being  seen,  while,  on  the  other  hand, 
acute  cases  may  show  the  change  in  every  tenth  corpuscle,  or  even  more 
often.  Like  polychromasia,  the  demonstration  of  basophilia  depends 
very  much  on  the  way  in  which  the  film  is  stained,  and  it  is  therefore 
very  important  to  treat  the  films  from  every  case  of  pernicious  anaemia 
in  exactly  the  same  way,  to  use  a  staining  solution  of  uniform  strength 
for  a  uniform  time,  and  to  make  the  time  of  washing  out  always  the 
same.  Prolonged  staining  and  prolonged  washing  may  destroy  both 
of  these  appearances.  Nucleated  red  corpuscles  occur  with  very  varying 
frequency.  One  can  seldom  reckon  on  finding  them  with  anything  like 
ease  if  the  red  count  be  above  2,500,000.  If  it  is  below  that  they  are 
always  to  be  discovered,  although,  in  some  of  the  chronic  cases  in 
particular,  a  prolonged  search  may  be  necessary,  extending  over  perhaps 
even  half  a  dozen  films.  They  are  almost  always  of  the  type  known  as 
megaloblasts.  Normoblasts,  in  our  experience,  are  rather  rare  in  the 
pernicious  anaemias  of  adults  at  any  rate.  In  children  they  are  more 
often  to  be  found.  The  type  of  megaloblast  varies  very  greatly.  The 
cell  is  always  large — from  two  to  four  times  larger  than  an  ordinary 
red  corpuscle — and  the  cell  body  may  stain  in  the  ordinary  way,  but 
often  shows  a  greater  or  less  degree  of  polychromasia,  or  even  basophilia. 
We  have  very  often  seen  basophilia  in  cells  dividing  by  mitosis.  The 
nucleus  may  be  large,  occupying  as  much  as  half  of  the  cell.  In  this 
case  it  is  pale,  and  the  intranuclear  reticulum  widely  spaced.  All 
variations  in  size  and  staining  may  be  seen  between  this  form,  which 
may  be  regarded  as  typical,  and  a  small  pyknotic  deeply-stained  homo- 
geneous nucleus  usually  situated  towards  one  edge  of  the  corpuscle. 
Forms  with  a  rounded  nucleus  occupying  a  little  less  than  one-third 
of  the  diameter  of  the  cell  are  very  common.  It  is  by  no  means 
infrequent,  especially  in  acute  cases,  to  see  cells  in  the  various  stages 
of  mitosis,  but  it  is  still  more  usual  to  find  the  nucleus  broken  up  into 
two,  three,  four,  or  more  parts,  connected  with  one  another  by  strands 
of  chromatin,  or  sometimes  separate — the  so-called  karyorrhexis,  a 
degenerative  change.  Some  authors  go  the  length  of  refusing  to  diagnose 
pernicious  anaemia  in  any  case  in  which  megaloblasts  cannot  be  found, 
and  it  is  certainly  wise  to  search  for  them  diligently,  yet  hardly  necessary 
to  examine  a  dozen  films  minutely  in  the  hope  of  finding  them  in 
chronic  cases  with  the  colour  index  just  above  1.  They  are  almost 
always  to  be  found  with  much  greater  ease  when  patients  are  going 
about,  or  within  the  first  day  of  their  stay  in  bed.  Thereafter  they  may 
entirely  disappear  from  the  blood  of  even  very  severe  cases.     Generally 


Plate  VII. — Blood  Film  from  Case  of  Pernicious  Anaemia  (Jenner's  Stain). 

The  average  size  of  the  red  corpuscles  is  increased.    Megaloblasts  (a,  b,  c)  are  present. 

(a)  Typical. 

(b)  Showing  mitosis  and  punctate  basophilia. 

(c)  Showing  very  marked  polychromasia. 
(f/)  A  microblast. 

(c)    A  pyknotic  normoblast  with  a  "Cabot's  ring "  and  granular  basophilia. 

(/)  Erythrocyte  with  punctate  basophilia. 

0/)   Erythrocyte  with  polychromasia  and  punctate  basophilia. 

(7()  Lymphocyte. 

(/.■)  Collection  of  blond-plates  ;  note  large  size. 


A.  G.,  fecit. 


PEENICIOUS   ANEMIA  135 

speaking,  one  finds  post-mortem  that  the  cases  which  showed  a  large 
number  of  megaloblasts  in  the  blood  during  life  show  a  large  number  in 
the  marrow.  While  the  rule  holds  good  that  cases  with  a  low  red 
count  are  more  likely  to  have  many  megaloblasts,  this  is  by  no  means 
invariably  true.  We  examined  recently  the  blood  of  a  patient  with 
a  red  count  of  600,000,  in  which  an  occasional  megaloblast  could  only 
be  found  after  much  search. 

Some  megaloblasts  are  found  of  extraordinary  size.  These  are  known 
as  gigantoblasts,  and  are  usually  said  to  indicate  a  bad  prognosis.  We 
have,  however,  seen  cases  recover  whose  blood  contained  them.  They 
generally  possess  a  large  open  nucleus.  Microblasts  are  found  in  some 
cases.  Their  origin  is  not  definitely  understood ;  they  generally  look 
like  degenerated  megaloblasts  or  normoblasts.  The  nucleus  is  small, 
sometimes  stains  deeply,  sometimes  hardly  at  all,  and  the  cell  body, 
instead  of  possessing  the  firm-looking  rounded  contour  of  the  other 
blasts,  is  usually  irregular  and  jagged,  and  shows  marked  polychromasia. 
They  are  seldom  found  unless  a  large  number  of  megaloblasts  are  to 
be  seen,  and  do  not  seem  to  possess  any  special  significance,  except 
as  nucleated  red  cells. 

The  Leucocytes. — As  might  be  expected  with  the  usual  low  count, 
there  is  generally  a  polymorph  leucopenia  or  relatively  high  lymphocyte 
proportion.  Such  a  proportion  as  polymorphs  40,  lymphocytes  60,  is 
very  common.  A  high  proportion  of  the  lymphocytes  are  of  the  small 
variety  ;  sometimes  no  larger  ones  can  be  found.  Eosinophils  are  often 
seen  in  about  the  normal  proportions.  It  has  been  stated  that  their 
presence  gives  a  good  element  to  prognosis,  but  we  have  not  been  able 
to  confirm  this.  Basophils  are  rare.  In  severe  cases,  and  sometimes 
just  before  death,  neutrophil  myelocytes  may  appear  in  small  number. 
The  polymorphs  are  often  large  and  oval,  with  a  nucleus  broken  up 
into  5,  6  or  more  lobes. 

The  Blood-Plates. — These  are  invariably  diminished  in  severe  cases, 
and  sometimes  seem  almost  to  disappear.  We  had  noticed  that  in  some 
cases  the  plates  were  much  larger  than  usual,  nearly  half  the  size  of  a 
red  corpuscle,  and  found,  in  conversation  with  Dr.  Cabot,  that  he  had 
made  the  same  observation.  The  reason  of  this  is  not  apparent,  but  so 
far  as  it  goes  it  tends  to  support  the  view  that  blood-plates  are  representa- 
tives of  the  nuclei  of  red  corpuscles.  As  cases  improve,  the  plates  become 
more  numerous,  and  sometimes  during  recovery, and  especially  at  the  stage 
of  low  colour  index,  may  be  as  numerous  as  in  a  secondary  anaemia. 

Staining  of  Blood-Plasma. — In  severe  cases  it  is  sometimes  found 


136  PEBNICIOUS   ANAEMIA 

if  Jenner's  stain  be  used  for  a  short  time  and  washed  out  rapidly  that 
the  dried  plasma  between  the  corpuscles  takes  on  a  light  blue  stain, 
with  a  clear  space  round  the  corpuscles.  This  is  sometimes  seen  also 
with  severe  secondary  anaemias,  but  never  so  well  marked. 

Alterations  in  the  Blood  during  the  Progress  of  the  Disease. — In  a  case 
which  is  going  downhill  the  behaviour  of  the  blood  will  vary  a  good  deal 
according  to  the  previous  acuteness  or  chronicity  of  the  case.  In  the 
acute  cases  the  tendency  is  for  the  corpuscles  to  diminish  steadily  in 
number  and  for  the  colour  index  to  rise,  or  at  any  rate  remain  high. 
More  and  more  megaloblasts  may  appear,  and  these  are  often  at  their 
maximum  just  before  death,  because  of  the  agonal  disturbance  of  the 
circulation.  They  may  be  found  also  in  large  numbers  if  the  blood 
taken  from  the  heart  at  a  post-mortem  examination  be  examined.  The 
red  count  with  which  patients  die  varies  very  considerably.  It  may  not 
have  fallen  below  1,000,000,  and  in  these  cases  patients  probably  die 
from  some  other  cause  than  the  anaemia.  In  other  cases  it  runs  down 
to  much  lower  figures.  We  have  only  once  seen  a  case  recover  where 
the  red  count  had  fallen  as  low  as  400,000,  but  that  patient,  after  being 
practically  comatose  for  nearly  a  fortnight,  picked  up  and  had  a 
remission  for  nearly  eighteen  months.  Quincke's  count  of  143,000  has 
never  been  equalled.  The  patient  in  that  case  recovered.  On  the  other 
hand,  in  the  chronic  cases  the  count  almost  never  falls  below  1,000,000, 
and  megaloblasts  are  often  very  scanty  indeed  even  as  death  approaches. 
The  leucocytes  usually  remain  at  about  the  same  figure  throughout, 
generally  with  a  slight  tendency  to  fall  towards  the  end.  We  have  very 
seldom  seen  an  agonal  leucocytosis. 

In  cases  which  are  going  to  recover,  the  red  corpuscles  sometimes 
increase  with  startling  rapidity.  There  may  be  a  rise  of  1,000,000 
a  week,  although  that  is  exceptional.  The  colour  index,  if  it  has  been 
high  when  the  patient  was  at  the  lowest  ebb,  gradually  drops.  If,  for 
example,  it  has  been  1*4,  at  the  end  of  ten  days  it  may  be  1*3,  and 
after  similar  intervals  1*2  and  l'l.  The  corpuscles  themselves  look 
more  natural,  basophilia  and  polychromasia  become  less  marked,  and 
megaloblasts  disappear.  A  certain  number  of  cases  never  reach  a 
completely  normal  blood,  and  seem  incapable  of  getting  beyond  about 
3,000,000  reds,  with  haemoglobin  of  65  or  70  per  cent.  These,  as 
a  rule,  have  but  a  short  period  of  comparative  health  and  soon  drop 
back  again,  but  a  certain  number  drift  into  the  chronic  form,  and  may 
last  in  that  way  for  a  long  time.  Cases  occasionally  show  marked 
improvement   in   symptoms   under  treatment,  with   little   or   no  real 


PEENICIOUS   ANEMIA  137 

improvement  in  the  blood.  "We  may  quote  the  case  of  a  man,  aged  42, 
who  had  great  weakness,  dilatation  of  the  heart,  oedema  of  the  legs, 
constipation  and  dyspepsia.  Eed  corpuscles  1,650,000,  haemoglobin  40, 
colour  index  1*2,  leucocytes  3800,  a  fair  number  of  megaloblasts.  In 
three  months  the  whole  of  the  alimentary  and  toxic  symptoms  had  dis- 
appeared. The  heart  was  no  longer  dilated,  and  the  oedema  had  gone. 
Eed  cells  1,700,000,  haemoglobin  45,  colour  index  1*3,  leucocytes  4000. 
Megaloblasts  had  disappeared.  Other  cases  reach  a  perfectly  normal 
count  in  every  way,  and  generally  do  so  by  passing  through  a  period 
of  relatively  low  colour  index.  A  typical  case  of  this  sort  might  have 
the  following  counts  at  successive  examinations  : — 


Beds. 

Haemoglobin. 

Colour  Index. 

1,500,000 

40 

1-3 

2,500,000 

60 

1-2 

3,500,000 

75 

1-07 

4,000,000 

80 

1-0 

4,500,000 

82 

0-9 

5,000,000 

85 

0-85 

5,000,000 

100 

1-0 

"We  have  seen  the  colour  index  drop  as  low  as  07,  and  it  sometimes 
remains  below  unity  for  weeks.  This  is  to  be  hailed  as  an  excellent 
omen,  for  such  cases  generally  have  a  long  remission — if  they  are 
careful.  But  though  the  count  may  be  satisfactory,  the  film  usually 
shows  some  departure  from  the  normal.  There  is  generally  a  greater 
amount  of  inequality  in  size  among  the  corpuscles  than  in  normal 
blood;  a  few  megalocytes  will  be  seen,  and  careful  search  will  generally 
find  some  polychromatic  corpuscles  or  some  punctate  basophilia.  "We 
have  occasionally  found  a  stray  megaloblast  in  cases  with  a  practically 
normal  count.  During  remission  the  leucocytes  seldom  stand  at  the 
normal  figure  of  7000.  They  may  remain  about  4000,  or  rise  to  5000 
or  6000 — the  higher  the  better  from  the  point  of  view  of  prognosis. 

It  is  very  difficult  to  get  a  large  mass  of  statistics  regarding  the 
behaviour  of  the  blood  as  patients  begin  to  go  downhill.  "We  find  that 
neither  patients  nor  doctors  will  take  the  trouble  to  have  regular 
examinations  of  the  blood  made  during  the  period  of  remission,  and, 
just  as  at  the  commencement  of  the  disease,  patients  do  not  usually 
come  under  observation  again  until  the  condition  is  well  established. 
"We  have  been  able,  however,  to  follow  a  few  cases  throughout,  and 
have  found  in  these  that  the  process  of  declension  is  a  gradual  one. 
The  red  corpuscles  drop  slowly  and  the  haemoglobin  rises  relatively. 
The  process   can  sometimes  be  arrested  by  treatment,  and   in  cases 


138  PEENICIOUS   ANEMIA 

which  do  not  respond  it  is  sometimes  found  that  there  is  an  attempt 
from  time  to  time  at  recovery  which  is  not  sustained. 

Diagnosis. — From  what  has  been  said  already,  it  will  be  evident  that 
this  always  depends  on  the  complete  examination  of  the  blood,  and  that 
there  is  no  certainty  to  be  attained  unless  this  is  properly  done.  The 
number  of  cases  which  present  the  classical  clinical  appearances  does 
not  reach  a  half  of  the  total  number,  and  it  is  wasting  precious  time  to 
wait  until  they  do  so,  if  indeed  they  ever  would  do  so.  The  disease 
is  vastly  more  common  than  is  generally  supposed,  and  seems  to  be 
becoming  more  frequent.  This  statement  is  based,  not  on  the  obvious 
cases,  which  naturally  find  their  way  to  professed  haematologists,  but  on 
the  number  of  cases  found  by  systematic  examination  of  the  blood, 
whose  condition  does  not  suggest,  or  suggests  only  to  the  practised  eye, 
the  possiblity  of  anaemia,  and  who  may  appear  to  be  suffering  from  the 
most  various  conditions.  What  will  be  said  under  the  heading  of 
"  Complications  "  is  of  importance  in  this  connection.  The  blood  should 
be  examined  in  every  case  which  presents  persistent  and  unexplained 
gastric  or  intestinal  disturbance,  especially  if  there  be  vomiting, 
diarrhoea,  or  sore  tongue.  Atypical  chronic  nervous  symptoms  of  any 
kind,  but  especially  if  they  are  associated  with  the  sensory  apparatus, 
the  peripheral  nerves  or  posterior  columns  of  the  cord,  unexplained 
debility,  temperature,  or  dyspnoea  should  indicate  a  blood  examination. 
The  point  is  that  the  disease  is  easily  missed  if  one  is  not  on  the  lookout. 

In  cases  which  are  definitely  anaemic  the  same  rule  holds — examine 
the  blood  fully.  High  colour  index  and  the  presence  of  megaloblasts 
are  the  principal  criteria,  and  leucopenia  is  a  definite  help.  No  clinical 
phenomena  can  be  relied  on  with  certainty.  For  example,  certain  cases 
of  gastric  cancer,  with  the  tumour  in  an  inaccessible  position,  simulate 
pernicious  anaemia  with  almost  absolute  fidelity.  The  colour  of  the 
skin,  the  gastric  disturbance  and  vomiting,  the  weakness  and  dyspnoea, 
the  absence  of  free  hydrochloric  acid  after  a  test-meal,  systolic  murmurs 
in  the  heart,  are  common  to  both,  and  we  have  often  left  a  patient's 
bedside  satisfied  that  we  had  to  deal  with  one  or  other  of  these  con- 
ditions, until  the  blood  examination  convinced  us  of  error.  Chlorosis 
is  not  worth  discussing.  The  colour  index  is  always  so  low  that  a 
mistake  is  hardly  possible.  It  is  different,  however,  with  the  severe 
secondary  anaemias  due  to  septic  infection,  haemorrhage,  or  concealed 
malignant  disease.  In  the  great  majority  of  cases,  of  course,  the  history 
and  clinical  phenomena  point  the  way,  but  where  these  are  doubtful 


PEENICIOUS  ANAEMIA  139 

there  may  be  a  temporary  hesitation.  The  reason  for  this  is  that, 
as  pointed  out  in  discussing  the  secondary  anaemias,  the  lower  the  blood 
runs  down  the  higher  the  colour  index  tends  to  become,  and  the  more 
large  red  corpuscles  appear  in  the  blood.  The  megaloblastic  reserve 
is  more  drawn  upon  and  the  megaloblasts  turn  out  megalocytes  into 
the  circulation  instead  of  dividing  to  form  normoblasts.  The  index  in 
these  secondary  cases  never,  in  our  experience,  reaches  unity,  however, 
but  tends  to  be  about  0*7,  or  at  the  highest  09,  and  in  the  enormous 
majority  of  these  cases  there  is  leucocytosis.  The  difficulty  is  most 
common  in  cases  of  anaemia  in  the  puerperium  and  in  septic  endocarditis 
without  any  obvious  primary  cause.  As  regards  the  first,  practitioners 
are,  naturally  enough,  most  unwilling  to  admit  the  possibility  of  sepsis, 
and  the  well-known  fact  that  pernicious  anaemia  does  occur  in  puerperal 
women  is  used  to  cover  a  multitude  of  discrepancies  in  the  blood 
examination.  In  both  these  diseases  the  anaemia  may  be  very  rapid 
in  its  onset — more  rapid  than  in  any  pernicious  anaemia.  We  have 
indeed  seen  septicaemias  whose  red  cells  had  dropped  from,  presumably, 
the  normal  figure  to  2,500,000  in  three  days.  When  nucleated  reds 
are  present,  as  they  often  are,  they  are  either  exclusively  normoblasts, 
or  towards  the  end  of  the  disease  a  few  megaloblasts  may  appear. 
Leucocytosis,  with  a  high  polymorph  percentage  and  a  well-marked 
glycogen  reaction,  is  practically  constant  except  in  the  intense 
fulminating  cases  which  are  so  rapidly  fatal  that  the  suspicion 
of  pernicious  anaemia  does  not  arise. 

A  word  of  warning  must  be  said,  however,  with  regard  to  colour 
index.  Figures  are  dangerous  things  unless  they  are  correct.  We  have 
found  that  mistakes  are  more  frequently  made  in  estimating  haemoglobin 
than  in  counting  reds,  and  we  would  protest  against  the  use  of  Tallqvist's 
haemoglobin  scale  in  the  diagnosis  of  pernicious  anaemia,  unless  it  is 
checked  by  a  more  accurate  haemoglobinometer.  It  almost  always 
reads  too  high,  and  the  tendency  of  the  inexperienced  is  to  make  it 
read  higher  still — we  have  seen  readings  by  youthful  enthusiasts  20 
and  30  per  cent,  too  high.  Less  than  this  might  convert  a  colour  index 
of  0*7  into  one  above  unity.  Some  people  have  a  congenital  inability 
to  match  colours,  and  these  persons  are  specially  liable  to  make 
errors  with  the  paper  scale.  They  should  always  use  one  of  the  liquid 
methods  in  which  transmitted  light  is  used,  for  slight  differences  in 
shade  are  then  much  more  obvious  than  they  are  with  the  opaque 
methods. 

A  difficulty  of  another  kind  sometimes  occurs  with  leukaemias  which 


140  PERNICIOUS   ANEMIA 

have  reached  the  stage  of  marked  anaemia.  As  noted  elsewhere,  the 
colour  index  may  then  rise  to  unity  or  just  below  it,  and  if,  for  some 
reason,  such  as  a  febrile  complication  or  X-ray  treatment,  the  number 
of  leucocytes  falls  to  normal  or  below  it,  the  diagnosis  might  be  in 
doubt  if  the  case  were  seen  for  the  first  time.  But,  generally  speaking, 
though  the  number  of  leucocytes  falls,  the  proportions  remain  abnormal, 
and  the  abnormal  cells  present  would  help  in  the  diagnosis.  The 
ordinary  clinical  appearances  in  the  case  would  also  be  helpful. 

Sometimes  practitioners  send  one  films  with  the  request  for  a 
diagnosis  of  pernicious  anaemia  or  otherwise.  In  some  cases  it  is 
quite  easy  to  give  an  opinion,  especially  if  many  megaloblasts  be 
present,  in  others  quite  impossible  if  these  cells  are  absent  and  if 
the  colour  index  be  just  about  unity.  A  haemoglobin  estimation  made 
at  the  same  time  is  a  great  help,  if  it  is  reasonably  accurate,  for  in 
practically  all  other  chronic  anaemias  the  reds  are  small  and  poorly 
shaped,  so  that  an  apparently  normal  film,  with  a  low  haemoglobin 
value,  should  always  arouse  the  suspicion  of  pernicious  anaemia. 

But,  of  course,  in  every  case  where  it  is  at  all  possible,  the  diagnosis 
should  be  based  on  a  complete  blood  examination. 

Complications. — While  the  disease  as  such  has  few  complications,  it 
is  often  complicated  in  the  most  various  ways.  This  statement  applies 
perhaps  especially  to  the  cases  occurring  in  later  life,  when  the  ordinary 
wear  and  tear  has  begun  to  tell  on  other  organs  besides  the  blood- 
forming  ones.  Here  the  anaemia  is  apt  to  be  of  a  chronic  type,  and  the 
additional  or  pre-existing  disease  bulks  much  more  largely  in  the  eyes 
of  both  doctor  and  patient.  Thus  we  have  seen  association  with  various 
forms  of  cardiac  valvular  disease,  with  angina  pectoris,  with  the  Stokes- 
Adams  syndrome,  with  arteriosclerosis ;  with  various  cancers,  as  of  the 
larynx  in  one  case,  of  the  stomach  in  one  case,  with  slow-growing 
scirrhus  of  the  breast  in  two  cases;  with  Bright's  disease  frequently, 
though,  as  we  have  remarked,  it  is  a  question  whether  the  kidney 
mischief  should  not  be  regarded  as  part  of  the  syndrome  of  pernicious 
anaemia ;  with  renal  and  hepatic  calculi ;  with  cystitis  very  often,  and, 
of  course,  with  prostatic  enlargement  and  its  results  in  old  men.  We 
have  seen  it  follow  upon  both  exophthalmic  goitre  and  myxcedema; 
and  we  might  indeed  enlarge  the  list  indefinitely ;  for  there  are  few 
of  the  ills  that  flesh  is  heir  to  which  may  not  be  interpolated  into  the 
course  of  the  disease,  or  precede  or  follow  it.  We  have  never  seen  it 
associated    with    active  tubercle,  nor,  judging  from    our   post-mortem 


PERNICIOUS   ANEMIA  141 

experience,  does  it  seem  to  have  much  association  with  healed 
tubercle.  Many  cases  are  cut  short  by  pneumonia,  influenza  and  septic 
complications.     Terminal  coma  is  common  and  is  sometimes  uraemia 

Duration  and  Course — Prognosis. — It  is  most  important  to  take 
into  consideration  the  cause  of  the  disease.  If  the  cause  can  be  dis- 
covered and  removed  the  outlook  is  good ;  if  not,  the  disease  will  sooner 
or  later  be  fatal.  The  cases  due  to  bothrioeephalus  latus  are  the  most 
satisfactory  in  this  respect.  The  cases,  too,  which  begin  during  preg- 
nancy or  the  puerperium  are  likely  to  recover  in  at  least  a  good  many 
cases  if  the  period  of  acute  symptoms  can  be  safely  tided  over.  The 
serious  element  in  these  cases  is  the  acute  onset. 

In  the  cases  in  which  no  cause  can  be  discovered  the  course  varies 
immensely.  It  is  difficult  to  say  how  short  the  duration  of  life  may 
be,  since  patients  are  practically  always  seriously  ill  before  they  are 
seen,  but  the  fatal  ending  has  come  in  fourteen  days  after  the  patient 
has  first  been  examined. 

It  must  not  be  taken  that  the  immediate  outlook  is  hopeless.  We 
have  had  patients  under  observation  for  over  twelve  years,  and  cases 
of  seventeen  and  twenty  years'  duration  are  on  record. 

One  of  the  remarkable  features  of  the  disease  is  the  occurrence 
of  remissions.  They  sometimes  begin  quite  abruptly  in  spite  of  severe 
symptoms,  the  red  corpuscles  increase  at  the  rate  of  200,000  per  day, 
and  in  a  few  weeks  a  patient,  apparently  at  death's  door,  appears  in 
good  health,  and  a  month  or  two  later  a  glowing  account  of  the  efficacy 
of  the  last  therapeutic  measure  employed  is  published  by  a  complacent 
editor. 

Eemissions  may  last  for  months  or  even  for  years.  A  patient  may 
undergo  as  many  as  half  a  dozen  remissions  and  relapses.  During  the 
remissions  the  chief  characteristics  of  the  blood  may  disappear,  but  in 
a  majority  of  cases  there  is  at  least  an  element  of  suspicion  in  the 
appearance  of  films,  even  though  the  red  cell  count  may  closely  ap- 
proximate the  normal  5,000,000.  In  many  cases  the  remission  is 
incomplete.  Patients  recover  so  far,  and  may  then  lead  a  life  of 
semi-invalidism  for  some  years. 

In  cases  that  are  going  to  do  well  there  is  often  a  loss  of  weight 
in  the  first  fortnight  of  treatment,  due  to  the  disappearance  of  oedema. 
The  disappearance  of  the  lemon-yellow  tint,  the  cessation  of  gastro- 
intestinal disturbance,  fall  of  temperature  to  normal,  are  all  favourable 
symptoms. 


142  PERNICIOUS   ANEMIA 

In  progressive  cases  there  is  a  general  decline  in  health  and 
strength.  Pallor,  oedema,  and  weakness  increase.  The  patient  be- 
comes first  unwilling  and  then  unable  to  leave  his  bed.  Cardiac 
excitement  is  brought  about  by  slight  disturbance.  Attacks  of  gastro- 
intestinal irritation  may  add  to  the  patient's  misery.  Sometimes  these 
symptoms  develop  with  startling  rapidity.  They  may  be  accompanied 
by  jaundice,  and  the  patient  seems  to  be  overwhelmed  by  an  intense 
toxaemia.  In  other  cases  there  is  increasing  weakness,  some  cachexia, 
apathy,  and  indifference,  followed  by  coma  and  death. 

In  a  disease  with  such  diverse  possibilities  it  is  important  to  be 
able  to  try  to  form  some  opinion  as  to  the  probable  immediate  outcome 
of  the  disease. 

The  age  of  the  patient  or  the  incidence  of  such  symptoms  as  sick- 
ness or  diarrhoea,  increase  of  the  yellow  tint  or  oedema,  does  not 
necessarily  affect  the  ultimate  course  of  the  disease. 

Febrile  attacks  add.  to  the  seriousness  of  the  condition  while  they 
last.  The  patient  may  not  be  any  the  worse,  and  is  sometimes  better 
after  they  are  over. 

Haemorrhages  are  a  serious  sign.  It  has  been  suggested  that  the 
retinal  haemorrhages  are  not  so  serious  prognostically  as  the  others. 

The  examination  of  the  blood,  and  particularly  the  repeated  examina- 
tion of  the  blood,  may  give  important  information.  Thus  a  case  whose 
corpuscles  are  well  under  1,000,000 — say  800,000— rarely  continues  long 
at  that  stage.  If  the  corpuscles  have  shown  a  distinct  tendency  to  fall 
in  about  a  fortnight,  we  may  predict  a  fairly  early  termination. 

On  the  other  hand,  if  the  tendency  of  the  corpuscles  is  to  rise, 
we  generally  find  that  our  case  will  fall  into  one  of  two  groups : — 

(a)  If  the  symptoms  are  well  marked,  we  may  expect  a  fairly 
satisfactory  remission. 

(b)  If  symptoms  are  not  marked — dyspnoea,  yellow  colour,  and 
fever  absent  or  slight — the  case  will  probably  run  a  somewhat  chronic 
course.  The  corpuscles  will  reach  to  between  one  and  two  million 
or  higher,  and  remain  at  that  point,  it  may  be,  for  years. 

When  the  blood  changes  are  considered  along  with  symptoms  we 
find  that  most  cases  will  fall  into  one  or  other  of  the  following 
groups : — 

I.  Acute  Favoukable  Cases 

1.  The  symptoms  are  marked. 

2.  Pied  cells  are  much  diminished,  but  show  a  tendency  to  rise. 


PERNICIOUS   ANiEMIA  143 

3.  Megaloblasts  are  atypical  and  not  numerous. 

4.  Normoblasts  are  relatively  numerous. 

5.  The  colour  index  is  high  but  tends  to  fall. 

6.  Poly chromatoph ilia  is  not  marked. 

7.  The  percentage  of  polymorphonuclear  cells  is  high,  and  the  white 
count  is  not  greatly  diminished. 

8.  Myelocytes  are  absent  or  scanty. 

Course. — A  remission  to  a  fairly  normal  condition,  which  may  be 
maintained  for  years. 

II.  Acute  Unfavoubable  Cases 

1.  Symptoms  are  marked,  and  there  may  be  haemorrhages. 

2.  Eed  cells  are  about  one  million,  and  tend  to  remain  or  go  lower. 

3.  Megaloblasts  are  typical  and  numerous. 

4.  Normoblasts  are  less  numerous  than  megaloblasts,  or  are  absent. 

5.  The  colour  index  is  high. 

6.  Polychromatophilia  is  marked. 

7.  Percentage  of  lymphocytes  is  high  and  there  is  marked  leucopenia. 

8.  Myelocytes  may  be  numerous. 

Course. — A  fatal  termination  in  from  one  to  three  months. 


III.  Subacute  Cases 

1.  Symptoms  are  fairly  well  marked. 

2.  Red  cells  about  one  million,  showing  considerable  variations  in 
successive  counts. 

3.  Megaloblasts  are  fairly  numerous. 

4.  Normoblasts  are  scanty. 

5.  The  colour  index  is  high. 

6.  Polychromatophilia  is  distinct. 

7.  The  percentage  of  lymphocytes  is  high  in  the  absence  of  fever. 

8.  Myelocytes  are  fairly  numerous. 

Course. — The  average  duration  is  about  two  years,  but  complications 
may  cut  it  short. 

IV.  Cheonic  Cases 

1.  Symptoms  are  not  well  marked. 

2.  Red  cells  tend  to  remain  about  one  and  a  half  or  two  million. 


144  PERNICIOUS   ANEMIA 

3.  Megaloblasts  are  absent  or  scanty. 

4.  Normoblasts  are  seldom  seen. 

5.  The  colour  index  is  generally  about  1. 

6.  Polychromatophilia  is  slight. 

7.  The  percentage  of  lymphocytes  is  high. 

8.  Myelocytes  are  scanty  or  absent. 

Course. — Apt  to  be  chronic.  Patients  can  often  work  though  they 
feel  weak ;  and  though  febrile  attacks,  etc.,  may  occur,  they  have  little 
bad  effect.  Symptoms  of  nerve  degeneration  are  not  uncommon,  but 
their  incidence  does  not  affect  prognosis.  Improvement  seldom  occurs, 
but  the  duration  may  be  for  several  years. 

Treatment.  —  The  first  essential  when  the  diagnosis  has  been 
definitely  made  is  to  approach  the  treatment  in  a  hopeful  spirit,  and 
not  to  allow  oneself,  or  the  patient,  to  be  depressed  by  the  adjective 
in  the  name  of  the  disease.  Too  often  the  diagnosis  is  followed  by 
the  perfunctory  prescription  of  arsenic  and  iron,  with  very  little  else 
in  the  way  of  treatment,  and  the  gradual  sinking  of  the  patient  is 
regarded  as  the  natural  course  of  the  disease  rather  than  as  being 
due  to  want  of  treatment.  As  a  matter  of  fact,  there  are  few  diseases 
of  so  serious  a  character  for  which  so  much  can  be  done  by  careful 
and  discriminating  therapeutics.  A  large  number  of  first  attacks 
will  get  well  with  almost  any  treatment  if  the  patients  are  placed 
under  proper  hygienic  conditions,  but  the  difficulty  of  recovery  increases 
steadily  in  most  cases,  in  geometrical  rather  than  in  arithmetical  pro- 
gression, with  each  successive  attack.  This  does  not  apply,  of  course,  to 
the  very  chronic  cases,  where  the  patients  live  for  years  in  a  state  of 
semi-invalidism  without  any  acute  symptoms,  and  in  which  the  blood 
never  can  be  got  up  to  the  normal. 

It  is  never  wise  to  tell  patients  that  they  are  suffering  from 
"  pernicious  "  anaemia,  but  they  must  be  informed  of  the  gravity  of 
the  condition,  in  order  that  they  may  intelligently  second  their  doctor's 
efforts. 

Rest, — ptest  is  of  great  importance  for  many  reasons.  Almost  every 
case  when  first  seen  is  suffering  more  or  less  from  chronic  cardiac  strain 
or  dilatation,  even  if  the  typical  fatty  change  be  not  present,  and  if  that 
is  allowed  to  continue  the  blood  will  not  improve.  The  digestion 
improves  with  rest ;  the  generalised  oedema,  which  is  so  common,  often 
disappears  with  rest  alone,  and  if  the  patient  can  be  spared  the  worries 
of  business  and  the  importunities  of  anxious  friends  improvement  is 


PERNICIOUS   ANEMIA  145 

more  likely.  Hospital  for  the  poor  and  conditions  as  nearly  as  possible 
approaching  those  of  hospital  for  the  well-to-do  are  of  great  value. 
Sunshine  and  fresh  air  are  potent  factors.  Patients  should  be  open- 
aired  as  freely  as  phthisis  cases  in  fine  weather,  but  they  must  be 
carefully  guarded  from  damp,  cold,  and  chill.  Bed  should  be  insisted 
on  until  the  haemoglobin  reaches  60  per  cent,  in  the  acuter  cases.  In 
the  more  chronic  cases  this  need  not  be  so  rigorously  enforced.  As  the 
patient  recovers  exercise  may  be  gradually  allowed,  but  its  effect  on 
the  heart  and  pulse  must  be  carefully  watched.  Even  after  complete 
recovery  patients  must  be  warned  that  they  must  take  life  more  easily 
than  before,  both  as  regards  work  and  play.  In  many  cases  recurrences 
are  directly  traceable  to  specially  strenuous  or  long-sustained  bodily  or 
mental  strain.  We  find  that  the  disease  is  apt  to  attack  energetic  men, 
who  in  the  joy  of  recovered  health  are  prone  to  attempt  to  make  up 
arrears  of  work,  and  so  relapse,  unless  they  are  specially  warned  of  the 
danger  of  overwork.  In  one  case  relapse  seemed  to  be  directly  due  to  a 
long  run  to  catch  a  train. 

Diet. — Diet  is  almost  equally  important.  In  every  acute  or  subacute 
case,  no  matter  whether  there  be  digestive  symptoms  or  not,  the  diet 
should  be  restricted  for  a  time  to  milk  and  farinaceous  foods.  Fish, 
meat,  poultry,  game,  meat  soups,  extracts  or  juices  must  be  rigidly 
tabooed.  One  often  finds  that  the  mere  exclusion  of  these  from  the 
diet  begins  improvement.  The  reason  for  this  is  probably  complex — 
the  anacidity  of  the  gastric  contents,  the  imperfect  intestinal  digestion, 
with  the  tendency  to  decomposition  of  the  contents  of  the  bowel,  the 
demands  made  on  the  already  overburdened  liver  by  the  heavier  nitro- 
genous foods,  and  the  temporary  or  permanent  alterations  in  the  kidneys 
which  we  have  shown  are  so  constantly  present,  and  which  are  probably 
due  to  the  excretion  of  toxins,  are  all  probably  factors  in  demanding  a 
simple  and  unirritating  diet.  The  details  of  the  menu  must  vary  with 
the  individual  case.  Patients  with  sickness  and  diarrhoea  may  require 
the  severely  simple  regime  of  peptonised  milk  alone,  and  may  gradually 
pass  through  the  usual  succession  of  Benger,  milk  puddings,  bread  and 
butter,  eggs,  etc.  Cases  with  constipation  often  benefit  by  the  addition 
of  vegetables,  stewed  fruit,  and  fruit  juices,  provided  these  are  not  so 
acid  as  to  upset  digestion.  Of  course  patients  tire  of  a  farinaceous  diet, 
and  the  length  of  time  during  which  it  must  be  persisted  with  varies 
greatly.  It  should  always  be  retained  as  the  staple,  even  after  return 
to  health,  but  a  certain  amount  of  the  more  digestible  meats  may  be 

allowed  as  improvement  takes  place.      In  patients  with  the  "  lemon- 

10 


146  PEENICIOUS   ANAEMIA 

yellow  "  tint  of  complexion  the  disappearance  of  this  colour,  which  is 
evidence  of  a  mild  toxic  hepatitis,  may  indicate  some  relaxation  in 
diet,  if  the  gastro-intestinal  symptoms  in  other  respects  are  improving. 
A  good  amount  of  fluid  should  usually  be  allowed  unless  there  be 
great  oedema.  Weak  tea  and  coffee  do  not  seem  to  be  harmful, 
but  alcohol  should  be  reserved  for  those  cases  and  emergencies  which 
require  it. 

Oral  Antiseptics. — In  a  disease  in  which  gastric  disturbance  is  so 
common  and  so  trying  a  symptom,  it  is  obvious  that  septic  conditions 
of  the  mouth,  teeth,  and  pharynx  should  always  be  carefully  treated 
whether  one  believes  that  they  have  anything  to  do  with  its  causation 
or  not. 

Intestinal  Antiseptics. — Intestinal  antiseptics  are  often  extremely 
serviceable  as  adjuvants.  Our  experience  has  been  that  a  com- 
bination of  small  doses  '  of  calomel  with  salol,  given  in  fairly  large 
doses,  is  most  useful ;  but  all  the  intestinal  antiseptics,  and  especially 
/3-naphthol,  have  been  tried,  and  are  of  service. 

In  cases  with  gastro-intestinal  symptoms,  moreover,  we  find  that 
excellent  results  are  often  obtained  by  washing  out  the  bowel  with 
physiological  saline,  the  amount  being  steadily  increased  as  the  lower 
bowel  is  cleared  out.  The  value  of  this  measure  is  as  great  in  cases 
with  diarrhoea  as  in  those  with  constipation,  and  it  is  usually  rapidly 
followed  by  disappearance  of  the  lemon-yellow  colour  and  by  return  of 
appetite.  We  make  it  a  routine  in  all  cases  when  they  first  come  under 
observation.  The  constipation  which  occurs  in  some  cases  seems  to 
be  atonic  from  muscular  anaemia.  Occasionally,  in  cases  with  severe 
vomiting,  we  have  washed  out  the  stomach  as  well ;  but  generally  the 
patients  are  too  weak  to  bear  this,  and  it  puts  too  great  a  strain  on 
the  heart. 

B.  Coli  Vaccines. — Some  cases  have  been  treated  with  B.  coli  vaccines 
prepared  from  the  patient's  fseces,  and  we  have  heard  of  cases  in  which 
good  results  have  been  claimed.  In  our  hands  the  measure  has  not 
been  successful. 

Arsenic. — As  regards  special  medicines,  arsenic  is  our  sheet-anchor. 
It  appears  to  act  mainly  by  stimulating  the  normoblastic  function  of 
the  bone-marrow,  but  perhaps  also  by  virtue  of  its  antiseptic  or  anti- 
toxic action.  It  is  best  given  in  solution,  either  as  Fowler's  solution 
or,  perhaps  better,  as  the  hydrochloric  solution,  which  is  usually  better 
borne  by  the  stomach.  It  may  be  necessary  sometimes  to  precede 
arsenic  by  a  course  of  gastric  sedatives.     The  dose  is  to  be  regulated  by 


PERNICIOUS   ANEMIA  147 

individual  tolerance,  and,  generally  speaking,  the  larger  the  dose  which 
can  be  taken  the  better  the  prognosis.     The  initial  dose  is  to  he  decided 
by  the  digestive  condition,  and  may  be  1  ]\  or  4  }\,  according  to  circum- 
stances, thrice  daily  after  food,  and  well  diluted  with  water.    The  initial 
dose,  say  4  }\,  should  be  given  for  three  days,  then  a  minim  added,  this 
again  for  three  days,  and  so  on  until  the  usual  symptoms  of  slight  over- 
dose begin  to  show  themselves.     The  arsenic  should  then  be  stopped 
altogether  for  two  or  three  days  until  the  symptoms  have  passed  off, 
and  then  recommenced  with  a  dose  two-thirds  the  size  of  that  reached, 
and  continued  at  that  level.     Thus  if  12  17^  cause  symptoms,  the  per- 
manent dose  should  be  8  1\.    Of  course  other  fluid  arsenical  preparations 
may  be  given,  or  the  solid  form  may  be  used,  but  it  is  not  so  easy  with 
this  to  graduate  the  dosage.     Occasionally  patients  who  cannot  tolerate 
arsenic  by  the  mouth  can  take  it  intramuscularly,  as  Fowler's  solution 
well  diluted.     A  single  daily  dose  is  generally  given.     Some  patients 
show  curious  idiosyncrasies  in  their  behaviour  to  arsenic.     It  may  be 
well  borne  for  a  time,  and  then  persistently  upset  digestion  in  spite 
of  all  that  can  be  done  to  aid  it  by  stomachics,  etc.     Or  the  reverse  may 
occur.     Or  a  patient  who  recovered  smoothly  from  a  first  attack  omder 
arsenic  may  be  quite  unable  to  take  it  in  a  second.     In  some  severe 
cases    the   attempt   to   push   arsenic  in  any  form   may  bring  oh  rise 
of   temperature,  with  or  without  gastric  disturbance.     Arsenic  should 
never   be   continued   after   the   red   count   has    reached    the    normal 
figure. 

The  desire  to  give  arsenic  in  large  doses  in  this  disease  without  the 
unpleasant  effects  which  the  inorganic  preparations  produce  has  led  to 
the  employment  of  all  the  organic  preparations  in  turn ;  cacodylate  of 
soda,  atoxyl,  soamin,  arsacetin,  and  the  rest  have  all  been  tried,  and  we 
experimented  largely  with  them  at  one  time.  We  were  not  satisfied, 
however,  that  the  cases  in  which  we  got  improvement  did  any  better 
than  they  would  have  done  with  ordinary  arsenic,  and  we  found  all  of 
them  in  turn  give  rise  to  much  more  serious  symptoms  in  certain  cases 
than  ordinary  arsenic  given  in  the  usual  way.  For  example,  with 
atoxyl  we  have  had  two  cases  of  very  severe  herpes,  a  well-marked 
arsenical  neuritis,  and  in  one  case  an  intense  febrile  reaction  with 
sickness,  vomiting,  and  diarrhoea,  which  lasted  for  several  days,  and 
which  recurred  when  a  quarter  of  the  original  dose  was  again  tried. 
In  short,  we  were  so  dissatisfied  with  all  these  preparations  that 
we  ceased  to  give  any  of  them,  and  fell  back  on  the  older 
method. 


148 


PEENICIOUS   ANAEMIA 


Salvarsan. — Since  Byrom  Bramwell  introduced  the  use  of  salvarsan 
in  the  treatment  of  pernicious  anaemia  a  large  number  of  cases  have 
been  reported.  In  a  recent  paper  Bramwell 1  records  eleven  cases.  Of 
these  four  improved  to  a  condition  of  health,  two  showed  marked 
improvement,  one  showed  slight  improvement,  two  did  not  improve, 
and  two  died. 

Salvarsan  was  injected  intramuscularly. 

Another  recent  series  of  eleven  cases  is  reported  by  Boggs.2  Two 
were  practically  moribund  before  the  treatment  and  died ;  the  remaining 
nine  cases  all  improved. 

Such  favourable  results  are  by  no  means  universal,  and  numerous 
cases  have  been  published  in  which  salvarsan  failed  to  benefit.  Our 
own  experience  is  not  encouraging.  In  the  following  tables  we  give 
a  note  of  our  results  in  twenty  cases. 

The  salvarsan  was  in  each  case  given  intravenously.  The  dose  in 
most  instances  was  06  grm.  In  one  or  two  cases  the  dose  was  smaller, 
and  in  several  of  the  cases  the  injections  were  repeated  more  than 
once. 

The  neo-salvarsan  in  the  cases  quoted  was  given  intramuscularly. 
The  dose  was  0*6  grm.  in  the  non-chronic  cases,  03  grm.  in  the  severer 
ones,  and  in  four  instances  the  dose  was  repeated  several  times. 

Salvarsan 


Sex. 

Age. 

Duration. 

Ked  Corpuscles 
in  millions. 

Haemoglobin 
per  cent. 

Result. 

Red  Corpuscles 

after 

Treatment. 

1. 

M. 

53 

4  years 

2-2 

50 

Improved 

4-3 

2. 

M. 

37 

15  months 

2-0 

58 

In  statu  quo 

1-4 

-3. 

M. 

28 

1  year 

2-0 

40 

Died 

0-3 

4. 

M. 

59 

9  months 

1-3 

30 

Died 

1-2 

5. 

F. 

33 

6  years 

1-7 

38 

Improved 

33 

6. 

M. 

50 

8  months 

2-4 

60 

In  statu  quo 

1-8 

7. 

M. 

68 

4  months 

2-2 

50 

In  statu,  quo 

2-3 

8. 

F. 

52 

3  months 

1-6 

38 

Improved 

4-3 

9. 

M. 

27 

1  year 

1-5 

35 

Died 

1-0 

10. 

M. 

50 

2  years 

1-6 

40 

Died 

1-5 

11. 

M. 

55 

3  months 

1-3 

28 

Died 

09 

12. 

F. 

61 

3  years 

2-6 

60 

Died 

1-5 

13. 

M. 

50 

2  years 

1-3 

28 

Died 

1-0 

1  Brit.  Med,  Journ.,  24th  May  1913. 

2  Johns  Hopkins  Med.  Bullet,  October  1913. 


PERNICIOUS   AK/EMIA 


149 


Neo-Salvarsan 


1. 

Sex. 

Age. 

Duration. 

Red  Corpuscles 
in  millions. 

Hfemoftlobin 
per  cent. 

Result. 

Red  Corpuscles 

after 

Treatment. 

M. 

44 

18  months 

1-3 

31 

In  statu  quo 

1-0 

2. 

F. 

56 

4  years 

2-8 

54 

Died 

2-7 

3. 

F. 

48 

6  months 

2-0 

30 

Improved 

3-9 

4. 

M. 

56 

3  years 

2-8 

60 

In  statu  quo 

2-5 

5. 

M. 

48 

8  months 

1-5 

40 

Died 

0-9 

6. 

F. 

40 

2  years 

.     24 

45 

Died 

1-7 

7. 

M. 

43 

6  months 

1-2 

33 

Died 

1-0 

Summary 


Salvarsan 
Neo-Salvarsan 

Improved. 

In  statu  quo. 

Died. 

Total. 

3 
1 

3 

2 

7 
4 

13 

7 

4 

5 

11 

20 

In  view  of  these  results  (and  we  have  no  knowledge  of  the  duration 
of  the  "  improvement "  recorded),  it  is  not  surprising  that  our  impression 
of  this  treatment  is  not  favourable. 

We  have  come  to  the  conclusion  that  neither  salvarsan  nor  neo- 
salvarsan  should  be  given  intravenously  in  acute  cases. 

The  injection  is  followed  by  a  reaction  which  affects  the  temperature 
and  the  heart  and  causes  gastro-intestinal  disturbance,  which  may  persist 
for  days.  We  have  little  doubt  that  in  some  of  the  very  acute  cases 
in  our  earlier  experience  of  the  drug  the  fatal  issue  was  hastened  by 
its  use.  In  more  recent  times  we  have  frequently  refused  to  sanction 
the  use  of  salvarsan  in  cases  of  this  sort  in  spite  of  the  importunity  of 
the  patient's  relatives  and  the  doctor  in  charge. 

In  subacute  and  chronic  cases  we  are  satisfied  that  no  better  results 
follow  the  use  of  salvarsan  than  ordinary  arsenic.  One  of  us  recently 
had  a  striking  illustration  of  this  in  hospital  practice.  Two  cases  of  the 
same  age,  with  similar  blood-counts,  and  in  apparently  much  the  same 
physical  condition,  were  admitted  within  a  week  of  each  other.  One 
case  received  five  intramuscular  injections  of  neo-salvarsan,  and  was 
afterwards  rather  worse  than  better.  The  other  case,  treated  with 
Fowler's  solution,  improved  steadily,  and  went  out  with  a  normal  blood- 
count  and  in  good  health.     Both  were  first  attacks. 


150  PEENICIOUS   ANEMIA 

After  an  intravenous  injection  of  either  salvarsan  or  neo-salvarsan 
a  reaction  is  to  be  expected  even  when  small  closes  have  been  employed. 
After  an  intramuscular  injection,  while  the  reaction  is  much  less  or 
absent,  local  pain  may  be  very  severe.  This  pain  may  be  all  the  greater 
because  of  the  enfeebled  condition  of  the  patient.  In  one  case  severe 
sciatica  was  complained  of  for  weeks  after  an  injection. 

If  other  measures  had  failed,  and  for  any  reason  we  were  inclined 
to  give  this  treatment  a  further  trial,  we  would  use  neo-salvarsan, 
because  of  the  greater  facility  of  dealing  with  it,  and  its  less  toxicity. 
"Whether  we  would  give  it  intravenously  or  intramuscularly  would 
depend  on  the  circumstances  of  the  case. 

Our  preference  would  be  for  intravenous  administration  in  small 
doses,  and  this  would  generally  be  our  choice  in  hospital  practice. 

If  the  symptoms  or  circumstances  of  the  case  were  such  that  we 
feared  the  effects  of  reaction  we  would  prefer  intramuscular  adminis- 
tration. 

We  do  not  attach  much  importance  to  the  view  that  intramuscular 
injection  is  to  be  preferred  because  the  drug  may  be  stored  in  the 
muscles,  and  thus  afford  the  body  a  continuous  supply  for  some  time. 
From  what  is  known  regarding  the  retention  of  arsenic  in  the  organs 
in  poisoning  cases,  we  hardly  think  the  method  of  administration  can 
make  much  difference  in  this  respect. 

Many  other  remedies  have  been  given,  and  cases  have  recovered 
with  their  use.  In  regard  to  all  of  them,  however,  we  would  again 
lay  stress  on  what  we  pointed  out  before,  that  in  a  first  attack  almost 
anything  may  cure,  provided  the  patient  be  under  proper  conditions ; 
and,  further,  that  the  course  of  the  disease  varies  so  greatly  that  it  is 
inadmissible  to  draw  conclusions  as  to  the  efficacy  of  any  remedy  from 
a  small  number  of  cases. 

Iron. — Iron  has  been  used  alone  and  in  combination  with  arsenic, 
and  in  cases  where  there  is  no  great  amount  of  gastro-intestinal  disturb- 
ance it  may  not  do  any  serious  harm,  but  is  not  needed,  as  there  is 
plenty  of  iron  stored  in  the  liver.  Where,  however,  there  is  sickness 
and  diarrhcea  it  undoubtedly  acts  as  a  poison,  and  should  be  avoided. 
There  is  one  period  in  the  course  of  pernicious  ansemia  where  iron  is, 
however,  very  useful,  and  that  is  when  a  patient  in  the  course  of 
recovery  has  attained  a  low  colour  index.  This  apparently  means  that 
he  has  used  up  all  the  iron  available  in  the  liver  and  elsewhere  and 
requires  more.     At  that  time  arsenic  is  of  little  or  no  service. 

Red  Bone-Marrow. — Eed  bone-marrow  has  been  given  raw,  cooked, 


PERNICIOUS   ANAEMIA  151 

dried,  and  in  various  extracts,  on  the  assumption  that  it  contains  a 
substance  which  stimulates  normoblastic  function.  In  most  of  the 
published  cases  in  which  it  is  said  to  have  been  successful  it  has  been 
given  along  with  arsenic.  When  we  have  given  it  alone,  as  we  fre- 
quently have,  we  have  never  been  able  to  satisfy  ourselves  that  it  had 
any  appreciable  effect,  although  others  appear  to  have  been  more 
fortunate.  Some  years  ago  a  friend  reported  a  case  to  us  which  had 
done  exceedingly  well  with  bone-marrow.  We  found  on  inquiry  that 
the  marrow  used  was  the  yellow  variety  ordinarily  supplied  by  the 
butcher ! 

Thorium  X. — A  few  cases  have  been  treated  with  thorium  X.  It  is 
administered  in  water  by  the  mouth  or  by  subcutaneous  injection.  A 
quantity  corresponding  to  20,000  milligram  emanations  may  be  given 
three  times  daily.  A  few  recoveries  have  been  recorded,  but  the 
published  results  generally  are  not  favourable. 

Antistr&ptococcus  Serum. — A  great  deal  has  been  written  from  time 
to  time  about  the  value  of  antistreptococcus  serum.  Its  use  was  based 
on  the  mistaken  notion  that  the  disease  is  due  to  a  streptococcus  infection, 
and  in  most  of  the  cases  of  cure  by  it  that  have  been  published,  other 
remedies,  such  as  arsenic,  have  been  used  in  addition.  We  have  seen 
one  or  two  cases  which  recovered  under  its  use  alone,  but  these  are 
mostly  open  to  the  objection  that  we  have  already  stated,  that  first 
attacks  may  recover  with  almost  any  measure. 

Normal  Horse  Sertim. — We  have  largely  used  normal  horse  serum 
in  cases  which  did  not  respond  to  arsenic,  and  have  given  it  both 
hypodermically  and  by  the  mouth,  and  sometimes  with  very  good 
results.  It  may  be  given  every  day  in  doses  of  10  c.c,  apparently  with 
impunity,  as  we  have  never  seen  any  symptoms  of  anaphylaxis,  and  it 
should  always  be  tried  when  arsenic  fails.  If  it  be  given  by  the  mouth 
it  is  well  to  administer  it  at  a  time  when  the  stomach  is  empty ;  it  may 
be  diluted  at  the  time  with  normal  saline. 

Transfusion  of  Blood. — Transfusion  of  blood  is  another  time-honoured 
measure,  and  has  much  theoretically  to  recommend  it.  It  is  improbable 
that  the  corpuscles  themselves  are  of  use  in  respiratory  interchange ; 
they  are  almost  certainly  broken  down,  although  we  have  never  seen 
the  hemoglobinuria  which  authors  have  described  as  a  result  of  the 
measure.  The  blood,  which  should  be  obtained  from  a  young  healthy 
adult  if  possible,  acts  apparently  by  neutralising  the  circulating  toxin 
in  some  way,  and  it  has  been  found  that  the  actual  quantity  injected 
does  not  greatly  influence  the  result.     It  is  probable  that  normal  horse 


152  PERNICIOUS   ANEMIA 

serum  acts  in  somewhat  the  same  fashion.  We  have  generally  employed 
the  indirect  method,  in  which  the  blood  is  received  into  a  solution  of 
sodium  phosphate  and  then  injected  into  the  vein  of  the  patient.  In 
a  very  few  cases  the  result  has  been  brilliant  and  recovery  has  followed ; 
in  a  larger  number  there  has  been  temporory  improvement  with  sub- 
sequent declension,  and  repeated  transfusion  has  not  been  successful ; 
while  in  perhaps  the  largest  number  of  cases  there  has  been  no  good 
result.  It  is  always  worth  trying,  however,  as  a  last  resort,  if  for 
business  or  family  reasons  it  is  important  that  the  patient's  life  should 
be  prolonged  as  much  as  possible. 

Direct  arm-to-arm  transfusion  through  a  short  paraffined  glass-tube 
has  also  been  carried  out,  but  the  results  seem  to  be  no  better  than  by 
the  indirect  method,  and  it  is  much  more  difficult,  and,  except  in  skilled 
hands,  more  dangerous. 

"We  tried  the  method  of  injecting  blood  intramuscularly  in  three 
cases,  but  as  no  good  result  was  obtained  we  have  not  proceeded  further 
with  the  measure. 

Feasibility  of  Operations. — The  question  of  the  feasibility  of  surgical 
operation  sometimes  crops  up  in  connection  with  pernicious  anaemia. 

We  recently  saw  a  case  where  it  was  complicated  by  bleeding  fibroid 
tumours.  Each  haemorrhage  was  definitely  lowering  the  blood  count. 
There  were  megaloblasts  and  polychromasia,  and  the  red  corpuscles 
numbered  1,370,000 ;  leucocytes,  4400  per  c.mm.  The  haemoglobin 
percentage  was  36,  giving  a  colour  index  of  T3. 

We  advocated  operation,  and  hysterectomy  was  successfully  per- 
formed. A  week  after  operation  the  red  corpuscles  numbered  1,600,000, 
and  the  haemoglobin  amounted  to  43  per  cent. 

In  another  case,  a  lady,  the  subject  of  pernicious  anaemia,  underwent 
an  operation  for  gall-stones,  when  her  red  corpuscles  numbered  3,500,000 
and  her  haemoglobin  percentage  was  72.  She  made  a  good  recovery  from 
the  operation,  and  the  course  of  the  anaemia  was  not  prejudiced. 

Such  cases  seem  to  show  that  the  subjects  of  pernicious  anaemia 
stand  operation  surprisingly  well,  but  it  is  certain  that  operations  may 
only  be  performed  when  the  reasons  for  them  are  very  urgent. 

Splenectomy. — Some  recent  cases  have  been  treated  by  splenectomy. 
The  subject  is  treated  in  an  appendix. 


CHAPTER  XV 

CHLOEOSIS 

Definition. — Chlorosis  or  green-sickness  is  a  disease  affecting  young 
women,  most  commonly  between  the  ages  of  fifteen  and  twenty-five, 
associated  with  breathlessness,  lassitude,  pallor  of  a  peculiar  type,  and 
certain  changes  in  the  blood. 

Etiology. — Chlorosis  is  a  disease  of  the  female  sex.  Cases  of 
anaemia  in  males  have  on  several  occasions  been  recorded  as 
instances  of  chlorosis.  While  the  symptoms  and  blood  changes 
may  show  a  close  resemblance,  we  agree  with  von  Noorden  that 
the  sex  gives  the  disease  its  distinctive  characteristics.  Age  is  an 
important  factor.  The  disease  usually  begins  between  fourteen  and 
twenty,  very  rarely  earlier  and  sometimes  later.  Anaemia  developing 
after  twenty-five  for  the  first  time  must  not  be  diagnosed  as  chlorosis 
without  very  substantial  reasons.  On  the  other  hand,  recurrences  of 
chlorotic  attacks  may  be  met  with  comparatively  late  in  life.  The 
disease  often  attacks  several  members  of  the  same  family,  and  girls 
in  large  families  seem  specially  liable.  A  history  of  chlorosis  in  the 
mother  is  often  obtained. 

Exciting  Causes. — In  a  small  proportion  of  cases  anything  in  the 
nature  of  an  exciting  cause  is  sought  for  in  vain,  and  the  predisposing 
factors  and  heredity  seem  to  offer  the  only  explanation  of  the  illness. 
It  is,  however,  more  common  to  find  a  history  of  bad  hygienic  con- 
ditions. Want  of  light  and  fresh  air,  and  overwork  are  frequent 
antecedents.  In  a  few  cases  want  of  exercise  is  the  outstanding 
factor,  but  the  disease  is  more  often  due  to  excessive  fatigue  than 
to  too  little. 

Want  of  proper  food  is  an  important  cause  of  chlorosis.  Actual 
privation  may  be  found,  but  more  frequently  the  condition  is  due  to  an 
indiscreet  dietary.  Girls  of  the  chlorotic  age  often  show  a  distaste  for 
flesh  food,  and  prefer  articles  of  diet  of  a  less  nutritious  character. 
Capriciousness  and  irritability  of  appetite  often  lead  to  a  large  con- 
sumption of  sweetmeats,  milk,  buns,  and  biscuits  at  odd  times,  with  the 


154  CHLOEOSIS 

result  that  meals  are  toyed  with  and  the  total  intake  of  nourishment 
is  insufficient  in  quantity  and  unsuitable  in  quality.  Dyspepsia  and 
constipation  may  add  to  the  effect.  Menorrhagia  appears  to  be  an 
exciting  cause  in  a  few  cases.  Mental  worry  and  home-sickness  have 
been  thought  to  give  rise  to  the  disease. 

The  condition  is  extremely  common  in  domestic  servants  and 
in  factory  workers,  especially  if  they  have  recently  come  from  the 
country  to  live  in  towns,  but  it  is  by  no  means  confined  to  the 
poorer  classes.  It  is  common  enough  in  wealthier  families,  though 
one  seldom  sees  in  them  the  severer  cases  met  with  among  the 
poor. 

There  seems  to  be  little  doubt  that  chlorosis  is  becoming  a  less 
frequent  condition  than  formerly.  This  may  be  ascribed  to  improved 
hygienic  conditions  in  the  kitchen  and  in  the  factory  and  to  the  passing 
of  the  sampler  and  the  "  accomplishments  "  in  favour  of  outdoor  sports 
among  girls  higher  in  the  social  scale. 

Pathology. — Chlorosis  is  not  a  fatal  disease,  hence  little  is  known 
of  its  morbid  anatomy.  Dilatation  and  fatty  degeneration  of  the  heart 
and  dilatation  of  the  stomach  have  been  found,  but  there  are  no  data 
regarding  the  condition  of  the  very  organs  that  it  is  most  desirable 
to  know  about. 

The  outstanding  facts  concerning  the  blood  (which  will  be  discussed 
later)  are  the  comparatively  slight  diminution  of  red  corpuscles  per 
cubic  millimetre,  the  low  percentage  of  hemoglobin,  and,  according  to 
Lorrain  Smith,  a  very  large  increase  of  the  total  amount  of  plasma  in 
the  body. 

A  very  large  number  of  theories  have  been  advanced  in  order  to 
explain  the  nature  of  the  disease.  Among  these  may  be  mentioned 
the  following: — 

1.  That  the  condition  is  due  to  a  congenital  hypoplasia  of  the  heart 
and  vessels. 

2.  That  it  is  associated  with  a  congenital  hypoplasia  of  the  genital 
organs. 

3.  That  it  is  due  to  indigestion,  intestinal  putrefaction,  gastroptosis 
caused  by  corsets,  or  to  constipation. 

While  any  or  all  of  these  may  be  of  some  importance  in  determining 
the  onset  of  an  attack  of  chlorosis,  they  do  not  explain  the  condition. 
The  evidences  of  increased  intestinal  decomposition  are  wanting.  Con- 
stipation is  not  specially  common  among  chlorotics,  and  the  disease  is 


CHLOROSIS  155 

not  cured   by  purgatives.      There  is  no  evidence  of   increased  blood 
destruction. 

4.  That  it  is  due  to  loss  of  blood  in  the  form  of  multiple  minute 
haemorrhages,  especially  in  the  intestinal  mucous  membrane,  and  loss 
of  blood  by  menstruation. 

Such  a  view  is  difficult  to  disprove,  but  there  seems  just  as  little  in 
its  favour  as  against  it. 

5.  That  the  symptoms  are  an  expression  of  neurosis. 

6.  That  the  disease  is  due  to  an  infection.  The  slight  increase  of 
splenic  dulness  appears  to  be  the  only  reason  for  this  suggestion,  but 
it  would  be  suprising  indeed  in  these  days  if  it  had  not  been  put 
forward. 

7.  That  it  is  due  to  a  functional  weakness  or  deficiency  of  the  bone- 
marrow.  In  connection  with  this  view  it  has  been  suggested  that  the 
marrow  may  prove  unequal  to  supplying  the  loss  of  blood  which  takes 
place  when  menstruation  is  established.  Along  with  this  loss  there  is 
often  an  insufficient  intake  of  iron  in  the  food.  It  has  further  been 
suggested  that  there  may  be  a  loss  or  disturbance  of  an  internal 
secretion  (probably  derived  from  the  ovaries)  which  is  supposed  to 
stimulate  the  bone-marrow  in  ordinary  circumstances.  Polzl1  has 
recently  shown  that  there  is  an  increase  of  red  corpuscles  before 
each  menstrual  period. 

8.  Lorrain  Smith  has  found,  as  the  result  of  observations  with  the 
carbon  monoxide  method,  that  the  total  amount  of  blood  plasma  is 
greatly  increased,  and  there  may  actually  be  an  excess  of  red  corpuscles 
and  haemoglobin  in  the  body  although  the  amount  per  unit  of  plasma 
is  deficient. 

The  last  two  views  require  further  consideration. 

Bone-Marrow  Deficiency. — This  may  be  regarded  as  the  classical 
view  of  the  nature  of  the  disease,  and  it  certainly  accords  well  with 
the  known  facts.  In  its  favour  is  the  fact  that  the  disease  begins  at 
an  age  when  a  special  strain  is  being  put  upon  haematogenesis,  and  an 
attack  often  follows  unhygienic  conditions.  The  symptoms  and  course 
accord  closely  with  the  deficiency  of  corpuscles  and  haemoglobin  in  a 
unit  of  plasma. 

The  small  size  of  the  red  cells,  their  poverty  in  haemoglobin,  the 
absence  of  polychromasia,  and  the  rarity  of  nucleated  red  cells,  as  well 
as  the  reduced  percentage  of  polymorphonuclear  cells,  all  point  in  the 
direction  of  insufficient  activity  on  the  part  of  the  bone-marrow. 
1  Munch,  med.  Wochenschr.,  1910,  333. 


156  CHLOEOSIS 

The  ready  curability  of  the  disease  with  iron  is  more  easily  explained 
on  this  hypothesis  than  on  any  other. 

Excess  of  Plasma. — Lorrain  Smith1  regards  an  increase  of  the  plasma 
as  the  essential  cause  of  the  blood  condition  and  the  symptoms.  At  the 
same  time  the  total  oxygen  capacity  or  total  amount  of  haemoglobin  is 
approximately  normal.  Taking  into  account  the  increase  in  the  amount 
of  plasma  and  the  number  of  corpuscles  per  cubic  millimetre,  there 
must  be  a  large  increase  in  the  total  number  of  red  and  white  cells  in 
the  body.  It  is  regarded  as  probable  that  in  the  earlier  stages  signs 
of  the  increase  of  plasma  are  hidden  as  far  as  the  corpuscles  are  con- 
cerned by  an  increase  in  their  number.  Each  one,  however,  contains 
less  than  its  full  complement  of  haemoglobin,  consequently  the  indica- 
tion of  the  disease  is  the  diminution  in  the  percentage  of  haemoglobin  in 
the  blood-unit — the  cubic  millimetre.  It  is  suggested  that  the  increase 
of  corpuscles  is  an  attempt  at  compensation  in  the  presence  of  excessive 
plasma.  There  is  no  such  compensation  in  regard  to  the  haemoglobin  per 
cubic  millimetre.     Later  the  compensation  in  corpuscles  also  fails. 

The  relation  of  the  leucocytes  to  the  increase  in  volume  differs  from 
that  of  the  red  corpuscles.  They  maintain  approximately  normal 
numbers  because  they  increase  in  direct  proportion  to  the  increase 
in  plasma.  In  favour  of  this  view  it  is  pointed  out  that  as  a  large 
volume  of  blood  has  to  be  sent  round  the  circulation,  greatly  increased 
work  is  thrown  on  the  heart,  and  the  value  of  a  unit  of  blood  for 
respiratory  exchange  is  diminished.  This  would  account  for  the  cardiac 
symptoms  which  occur  in  many  cases  of  chlorosis.  The  increased 
amount  of  fluid  affords  an  explanation  of  the  functional  cardiac 
murmurs,  which  on  this  hypothesis  are  caused  by  overfilling  of  the 
chambers  of  the  heart,  and  a  consequent  relative  insufficiency  of  the 
valvular  orifices.  The  tendency  to  dilatation  is  of  course  helped  by 
the  anaemia  and  the  consequent  malnutrition  of  the  cardiac  muscle. 
While  the  blood  as  a  whole  has  a  normal  capacity  for  oxygen,  the 
increase  in  quantity  renders  it  unwieldy  as  a  oxygen  carrier,  and  hence 
dyspnoea  is  a  prominent  symptom. 

Among  the  difficulties  which  suggest  themselves  in  the  way  of 
accepting  the  view  of  Lorrain  Smith  is  the  incidence  of  a  condition 
involving  an  increase  of  all  the  constituents  of  the  blood  as  a  sequel 
of  bad  feeding  or  hygiene.  The  elimination  of  body  fluids  is  so  rapid 
that  it  is  difficult  to  understand  why  such  a  condition  should  persist. 
The  great  increase  of  plasma  in  the  vessels  (sometimes  nearly  double 
1  Trans.  Path.  Soc.  London,  li.  1900,  311. 


CHLOROSIS  157 

the  normal)  might  be  expected  to  throw  an  increase  of  work  on  the 
heart,  which  should  give  rise  to  much  more  urgent  cardiac  symptoms 
than  ever  occur  and  a  higher  blood-pressure  than  has  ever  been  recorded. 
The  blood-pressure  is  practically  never  above  normal.  It  is  further 
difficult  to  understand,  on  Smith's  hypothesis,  why  the  disease  is  so 
amenable  to  treatment  with  iron  and  is  not  cured  by  the  use  of  purga- 
tives, and  why  the  body  weight  tends  to  increase  rather  than  diminish 
during  treatment. 

Apart  from  any  criticism  of  the  method,  an  important  factor  in 
influencing  the  result  appears  to  us  to  have  been  overlooked.  That 
factor  is  the  relationship  between  the  haemoglobin  in  the  marrow  and 
the  haemoglobin  in  the  circulating  blood. 

Haldane  and  Lorrain  Smith  admit  that  some  of  the  CO  inhaled  may 
be  taken  up  by  haemoglobin  in  muscle,  and  that  if  so  the  estimated 
total  amount  of  blood  will  be  excessive.  The  amount  in  muscle  is, 
however,  negligible.  It  is  surely  otherwise  with  the  marrow.  In  the 
marrow  the  proportion  of  haemoglobin  to  plasma  is  very  much  higher 
than  in  the  circulating  blood.  Error  from  this  source  is  probably  nearly 
a  constant  one  in  health,  but  in  disease  the  normal  relationship  between 
blood  and  marrow  is  disturbed.  In  chlorosis  the  corpuscles  are  poor 
in  haemoglobin.  There  is  no  likelihood  that  the  amount  of  red  marrow 
is  diminished,  and  it  is  possible  that  along  with  a  qualitative  deficiency 
there  is  a  compensatory  quantitative  increase.  (Lorrain  Smith's  view 
practically  postulates  this.) 

In  any  case  the  histology  of  the  blood  suggests  that  the  proportion 
of  marrow  to  circulating  corpuscles  is  increased,  and  this  state  of  affairs 
would  cause  the  estimate  of  total  volume  of  blood  by  the  CO  method 
to  be  unduly  high. 

This  criticism  has  recently  been  confirmed  by  Dreyer,  Eay,  and  Ainley 
Walker.1  They  conclude  that  the  CO  method  as  hitherto  employed  for 
determining  the  normal  blood  volume  cannot  be  relied  upon,  since  the  results 
which  it  yields  are  not  only  out  of  accord  with  those  obtained  by  direct 
methods  of  estimating  the  blood,  but  also  exhibit  marked  disagreements 
among  themselves. 

They  say  that  "  where  the  normal  ratio  between  circulating  intravascular 
haemoglobin  and  extravascular  haemoglobin  is  disturbed  either  by  the 
diminution  of  the  intravascular  haemoglobin  or  by  the  increase  of  extra- 
vascular  haemoglobin  caused  by  increased  activity  of  the  blood-forming 
organs,  or  by  the  deposit  of  unusual  quantities  of  haemoglobin  or  other 
CO-combining  substances  in  various  organs,  the  partition  co-efficient  of  CO' 

1  Skanclinav.  Archiv.  f.  Physiologie,  1913,  299. 


158  CHLOEOSIS 

will  inevitably  be  altered.  Accordingly  the  results  obtained  can  never  yield 
accurate  information  regarding  the  actual  volume  of  the  blood  in  conditions 
of  disease  affecting  the  blood.  At  best  it  can  only  give  a  measure  of  the 
total  quantity  of  CO-combining  substances  in  the  body." 

This  is  in  essence  just  what  we  have  written  above. 

These  authors  also  state  that  it  is  difficult  to  escape  the  conclusion  that, 
owing  to  the  use  of  the  CO  method,  Lorrain  Smith's  careful  and  laborious 
investigation  of  chlorosis  yielded  results  which  cannot  be  accepted  till  new 
experimental  evidence  is  brought  forward  to  support  them. 

Symptoms. —  Chlorosis  may  develop  very  rapidly,  even  in  the 
course  of  a  few  days.  More  frequently,  however,  the  incipient  stage 
extends  over  two  or  three  weeks.  The  first  symptom  complained  of 
is  usually  breathlessness  on  exertion.  Fatigue,  drowsiness,  and  palpi-  ■ 
tation  soon  develop.  Pallor,  associated  with  a  peculiar  greenish  tint, 
does  not  usually  appear  till  the  blood  changes  are  well  marked.  It 
shows  first  in  the  lips  and  conjunctivae,  later  in  the  skin.  When  the 
condition  has  become  established  a  great  variety  of  symptoms  may 
be  noted.  The  temperature  seldom  rises  unless  some  complication 
occurs. 

Alimentary  System.  —  The  amount  of  disturbance  varies  greatly. 
Some  patients  retain  a  normal  appetite,  and  these  tend  to  become 
fat ;  others  lose  their  appetite  and  become  thin.  In  either  case  great 
caprice  is  often  exhibited  in  the  choice  of  food.  Meat  is  generally 
disliked.  Sour  or  acid  substances,  such  as  lemons  and  vinegar,  may 
be  taken  in  large  quantities.  Starch,  dry  oatmeal,  or  sago  may  be  taken, 
and  in  some  cases  tea  leaves,  chalk,  or  even  earth  may  be  eaten. 

The  tongue  is  usually  pale  and  clean,  but  may  be  furred  and  flabby. 
The  stomach  is  sometimes  dilated,  and  gastric  ulcer  is  a  common  com- 
plication. The  total  acidity  and  proportion  of  free  hydrochloric  acid 
in  the  stomach  contents  after  a  test  breakfast  are  practically  never 
below  high  normal  values,  and  may  be  considerably  above  these. 
Constipation  is  common. 

Hemopoietic  System. — The  splenic  dulness  is  often  enlarged,  but  the 
organ  is  rarely  palpable.     Lymphatic  glands  are  not  enlarged. 

Circulatory  System. — The  patient  complains  of  breathlessness  on 
exertion.  In  some  cases  fainting  occurs  on  slight  provocation,  and  is 
common  after  prolonged  standing.  The  pulse  is  generally  rapid.  Cold 
feet  and  numbness  of  the  fingers  from  weakness  of  the  peripheral 
circulation  are  often  complained  of.  At  the  same  time  the  vessels  are 
•excitable,  and  patients  readily  flush.     In  severe  cases   there  may  be 


CHLOROSIS  159 

some  oedema  of  the  ankles.  The  area  of  cardiac  dulness  is  increased, 
particularly  towards  the  right  side.  This  is  due  in  some  cases  to 
dilatation  of  the  heart,  but  in  others  it  is  to  be  accounted  for  by 
retraction  of  the  lungs  due  to  superficial  breathing.  This  pulmonary 
retraction  accounts  for  the  unduly  loud  pulmonary  sounds  which  are 
sometimes  heard.  Examination  of  the  heart  by  X-rays  indicates  that 
it  is  more  frequently  displaced  by  shrinkage  of  the  lung  and  a  high 
diaphragm  than  actually  dilated.  Pulsation  is  often  to  be  seen  and  felt 
in  the  episternal  notch,  in  the  pulmonary  area,  over  the  right  ventricle, 
and  in  the  epigastrium. 

Cardiac  and  Vascidar  Murmurs. — The  cardiac  murmurs  of  chlorosis 
are  practically  always  systolic  in  time.  They  are  heard  most  frequently 
over  the  pulmonary  area,  with  the  point  of  maximum  intensity  in  the 
second  or  third  left  interspace  close  to  the  sternum.  Less  commonly  a 
systolic  murmur  is  best  heard  in  the  aortic  area,  and  systolic  murmurs 
are  sometimes  heard  in  the  tricuspid  area  or  in  the  mitral  area,  usually 
along  with  the  basal  murmur,  but  sometimes  alone.  The  cause  of  these 
murmurs  has  been  much  debated. 

The  most  commonly  accepted  view  regarding  the  basal  murmur  is 
that  it  is  due  to  a  want  of  tone  in  the  arterial  wall  caused  by  mal- 
nutrition, and  is  produced  by  the  sudden  propulsion  of  blood  into 
a  vessel  which  is  relatively  dilated  in  comparison  to  its  orifice.  The 
tricuspid  and  mitral  murmurs,  when  associated  with  basal  murmurs, 
are  probably  due  to  conduction,  but  when  alone  the  possibility  of 
dilatation  of  the  heart  to  such  an  extent  as  to  bring  about  such  a 
relative  insufficiency  of  the  valvular  orifice  as  to  cause  tricuspid  or 
mitral  regurgitation  must  be  considered. 

The  question  of  pre-existing  valvular  disease  may  be  a  very  difficult 
one,  but  is  eventually  cleared  up  by  the  result  of  treatment.  Chlorotic 
dilatation  is  readily  curable. 

Arterial  murmurs  are  sometimes  heard  at  a  distance  from  the  heart. 
Venous  murmurs  are  common,  and  are  most  easily  heard  in  the  jugular 
veins  at  the  root  of  the  neck,  especially  on  the  right  side.  The  murmur 
takes  the  form  of  an  almost  continuous  hum — bruit  de  diable.  It  is  best 
heard  when  the  patient  is  in  the  erect  posture. 

A  similar  venous  hum  may  sometimes  be  heard  over  the  eyeball, 
over  the  occipital  protuberance,  and  elsewhere.  It  is  very  characteristic 
of  chlorosis,  although  not  strictly  confined  to  it. 

Diastolic  cardiac  murmurs  in  chlorosis  have  been  described,  but 
occur  with   great   rarity.      They  are   heard   in   the   aortic   area,  and 


160  CHLOEOSIS 

are  to  be  accounted  for  by  transmission  from  the  great  veins  of 
the  neck. 

Venous  Thrombosis. — This  contingency  is  rare  enough  to  be  regarded 
as  a  complication  rather  than  a  symptom  of  chlorosis.  It  occurred  in 
6  out  of  431  of  von  Erben's  cases,  and  in  5  out  of  230  cases  recorded 
by  von  Nborden.  It  usually  affects  the  veins  of  the  leg  or  the  brain 
sinuses.  The  latter  contingency  accounts  for  practically  all  the  fatal 
cases  of  chlorosis.  Its  early  manifestations  are  unfortunately  very  likely 
to  be  mistaken  for  hysteria. 

Some  authors  have  regarded  the  optic  neuritis  which  occasionally 
occurs  in  chlorosis  as  being  caused  by  thrombosis  of  the  cavernous 
sinus. 

It  has  been  suggested  that  venous  thrombosis  is  more  common  in 
those  cases  of  chlorosis,  which  are  fairly  numerous,  in  which  the  blood- 
plates  are  increased  in  number,  and  that  they  become  agglutinated  in  the 
capillaries  so  as  to  form  capillary  thrombi,  which  act  as  the  starting- 
point  of  the  change  in  the  veins.  It  is  certainly  possible  in  some  of 
the  cases  with  an  increased  number  of  blood-plates  to  find  in  films 
long,  straight,  or  curved  cylindrical  masses  of  blood-plates  which  might 
well  have  been  washed  out  of  capillary  vessels.  In  looking  for  them 
special  care  must  be  taken  not  to  squeeze  the  cover-glasses  together 
in  making  the  films. 

Respiratory  System. — Breathing  is  hurried,  and  in  a  few  cases 
there  have  been  attacks  of  special  rapidity  of  respiration,  but  with- 
out the  accompanying  sensations  of  dyspnoea.  The  respirations  are 
shallow,  and  as  a  result  there  may  be  some  degree  of  retraction 
of  the  lungs,  and  the  diaphragm  is  at  a  slightly  higher  level  than 
normal. 

Integumentary  System. — The  pallor  and  the  tendency  to  flushing 
of  the  skin  have  already  been  referred  to.  Seborrhcea  and  acne  are 
commonly  found.  Urticaria  and  chilblains  are  very  frequent  in 
chlorotics. 

Genito-  Urinary  System. — The  urine  is  abundant,  pale,  and  has  a  low 
specific  gravity.  Menstrual  disturbances  are  very  frequent.  Menstrua- 
tion is  usually  scanty  or  in  abeyance.  Barely  it  is  increased.  Leucor- 
rhcea  is  fairly  common.  It  is  not  unusual  to  get  a  history  of  menorrhagia 
preceding  the  onset  of  the  disease,  followed  by  amenorrhcea  when  it  is 
established. 

Nervous  System. — Muscular  power  is  diminished.  Some  patients  are 
morose  and  apathetic,  and  many  such  cases  may  receive   but  scant 


CHLOEOSIS  161 

sympathy  from  their  relatives  before  the  fact  is  realised  that  the  girl 
is  ill.  Irritability  and  hysterical  attacks  are  not  uncommon.  In  severe 
cases  the  patient  is  constantly  tired,  and  so  drowsy  that  she  may  fall 
asleep  whenever  she  sits  down  in  a  chair.  Headache  is  frequent, 
and  in  severe  cases,  tinnitus,  temporary  deafness,  or  blindness  is  met 
with.  The  headache  may  be  constant,  or  may  occur  in  paroxysms. 
Optic  neuritis  sometimes  occurs,  often  without  any  disturbance  of 
vision.  Neuralgias  are  common.  Inframammary  neuralgia  is  perhaps 
most  frequent. 

The  Blood  Changes. — The  blood  when  drawn  is  pale  and  watery. 
The  specific  gravity  varies  with  the  amount  of  haemoglobin.  No  special 
change  has  been  found  in  connection  with  the  specific  gravity  of  the 
plasma  or  serum.  The  blood  coagulates  rapidly  although  fibrin  is  not 
increased. 

The  number  of  red  corpuscles  per  cubic  millimetre  varies  consider- 
ably. As  a  rule  the  number  when  patients  first  come  under  observation 
is  about  three  and  a  half  millions  in  severe  cases.  Not  infrequently 
the  number  is  normal — four  and  a  half  millions,  or  increased  up  to 
five  and  a  half  or  even  six  millions.  On  the  other  hand,  low  counts 
are  sometimes  met  with,  but  numbers  below  two  millions  are  very 
rare,  and  are  usually  to  be  explained  by  the  co-existence  of  some 
hemorrhagic  condition,  such  as  bleeding  piles,  gastric  ulcer,  or 
menorrhagia. 

In  cases  with  high  counts  it  will  generally  be  found  that  some 
condition  of  cardiac  debility  is  present — either  an  organic  lesion, 
usually  mitral,  or  more  commonly  chronic  cardiac  strain  or  dila- 
tation. 

The  amount  of  haemoglobin  is  always  diminished.  The  diminution 
is  not  only  absolute,  but  there  is  a  great  diminution  relatively  to  the 
red  corpuscles — in  other  words,  the  colour  index  is  always  low.  A 
fairly  common  relationship  is  a  red  count  of  4,000,000,  with  35  per 
cent,  of  haemoglobin,  giving  a  colour  index  of  0*43.  In  untreated 
severe  cases  the  colour  index  is  very  rarely  above  0*5,  but  in  slight 
cases  may  rise  to  0*6. 

The  following  table  gives  the  figures  in  twelve  successive  cases  seen 
in  an  outpatient  department : — 


11 


162 


CHLOEOSIS 


Age. 

Red  Cells  per  e.mm. 

White  Cells 
per  c.mm. 

Hb. 
per  cent. 

Colour 
Index. 

21 

3,000,000 

4062 

15 

0-25 

21 

3,582,400 

3125 

30 

0-42 

17 

4,270,000 

4687 

45 

0-54 

23 

4,150,000 

3516 

25 

0-3 

15 

3,800,000 

3125 

35 

•      0-46 

17 

4,500,000 

3515 

35 

0-38 

14 

3,880,000 

2148 

35 

0-45 

16 

3,080,000 

6586 

35 

0-57 

15 

2,938,000 

5312 

30 

0-51 

16 

3,589,600 

6250 

35 

0-49 

23 

2,320,000 

1870 

25 

0-54 

20 

3,200,000 

3750 

30 

0-46 

Leucocytes  are  always  decreased  in  number.  The  diminution  seems 
to  be  more  marked  in  the  more  severe  cases.  The  reduction  chiefly 
affects  the  polymorphs,  so  that  there  is  a  high  percentage  of  lympho- 
cytes, and  the  percentage  of  large  lymphocytes  is  often  specially 
increased.     Leucocytosis  always  indicates  some  complication. 

Blood-plates  are  always  increased  in  number,  and  sometimes  appear 
almost  as  numerous  as  the  red  corpuscles.  Capillary  thrombi  composed 
of  blood-plates  are  sometimes  seen  in  stained  films. 

The  red  corpuscles  show  a  distinct  diminution  in  their  average  size. 
Their  centres  are  much  paler  than  usual,  an  appearance  which  corre- 
sponds to  their  poverty  in  hsemoglobin.  In  mild  cases  there  is  not 
much  change  in  the  shape  of  the  red  cells,  but  in  severe  cases  they  may 
show  great  deformity.  The  poikilocytosis  may  exceed  that  usually  seen 
in  pernicious  anaemia,  but  the  corpuscles  are  all  small  and  show  the 
central  pallor.  Nucleated  red  cells  are  extremely  rare,  and  only  occur 
in  very  severe  cases.  Both  megaloblasts  and  normoblasts  have  been 
noticed,  but  megaloblasts  occur  so  rarely  that  their  presence  in  chlorosis 
may  be  regarded  as  a  curiosity. 

If  a  case  be  watched  throughout  its  course  of  development  and 
recovery  it  will  be  found  that  at  first  the  red  corpuscles  are  normal 
in  number,  but  their  complement  of  haemoglobin  is  deficient  and  they 
are  small  in  size.  At  a  later  stage  their  numbers  diminish  and  poikilo- 
cytosis appears.  As  the  case  improves  there  is  a  rapid  increase  in  the 
number  of  corpuscles,  but  they  remain  small  and  pale,  and  their  normal 
numbers  have  been  regained  long  before  they  become  of  normal  size  or 
contain  the  proper  amount  of  hsemoglobin. 


Course,  Prognosis,  Complications. — As  a  rule,  those  cases  which 


Plate  VIII. — Blood  Film  from  Case  of  Chlorosis  (Jenner's  Stain). 

The  average  size  of  the  red  corpuscles  is  diminished. 

There  is  marked  poikilocytosis. 

Blood-plates  are  increased.    At  (a)  plates  are  seen  superimposed  on  red  cells,  an  appearance  often 

mistaken  for  normoblasts. 
(h)  The  central  condensation  of  hnemoglobin  seen  in  a  few  erythrocytes. 


A.  a.,  fecit. 


CHLOROSIS  163 

have  a  rapid  onset  recover  most  quickly,  but  all  cases,  whether  acute  or 
chronic,  show  a  marked  tendency  to  recurrence.  In  an  ordinary  case 
the  attack  lasts  from  six  weeks  to  four  months,  but  in  a  great  many 
cases,  although  distressing  symptoms  have  disappeared  in  this  time, 
complete  restoration  to  health  has  not  occurred.  An  important  point 
in  regard  to  the  course  of  the  disease  is  that  patients  seldom  persist  long 
enough  in  a  course  of  treatment.  They  become  accustomed  to  a  condi- 
tion of  health  which  is  short  of  robustness,  and  hence  do  not  realise  the 
necessity  for  taking  drugs  after  the  more  acute  symptoms  have  dis- 
appeared. A  common  result  is  that  a  relapse  speedily  occurs,  and  it  is 
then  found  that  the  relapse  does  not  yield  to  treatment  so  readily  or 
completely  as  a  first  attack ;  thus  a  certain  number  of  these  cases  fall 
into  a  condition  of  semi-invaliclism. 

Cases  thoroughly  treated  recover  completely,  and  have  not  the  same 
liability  to  relapse  that  is  the  fate  of  those  only  partially  recovered. 

The  most  serious  aspect  of  chlorosis  is  that  if  it  persists  for  any  time 
it  renders  the  nutrition  of  the  body  imperfect  just  when  development  of 
body  and  mind  should  be  most  active,  with  the  result  that  both  may 
suffer.  Moreover,  chlorosis  is  apt  to  be  attended  by  complications  such 
as  gastric  ulcer  and  thromboses.  The  occurrence  of  exophthalmic  goitre 
in  cases  of  chlorosis  is  probably  more  frequent  than  could  be  accounted 
for  by  mere  coincidence.  There  is  a  greater  liability  to  the  infectious 
diseases,  and  convalescence  from  intercurrent  disease  is  prolonged. 

Diagnosis. — The  clinical  picture  is  usually  pretty  definite.  The 
outstanding  features  are  the  sex,  age,  the  history  and  general  appear- 
ance of  the  patient,  the  blood  changes,  particularly  the  low  colour  index, 
and  the  ready  response  to  treatment  with  iron.  Occasional  difficulty 
arises  from  an  unusual  prominence  of  one  or  more  groups  of  symptoms. 
The  gastric  and  cardiac  symptoms  and  those  associated  with  the  repro- 
ductive system  are  most  likely  to  lead  to  error.  A  very  real  difficulty 
sometimes  arises  in  cases  where  other  disease  co-exists.  Chlorosis  has 
to  be  distinguished  from  other  conditions  causing  antemia.  The  chief  of 
these  are  the  following  : — 

1.  Pernicious  anaemia  and  leucocythcemia  are  readily  distinguished  by 
the  blood-picture. 

2.  Anaemia  from  Intestinal  Parasites. — The  colour  index  is  not  likely 
to  be  so  low  as  in  chlorosis,  and  in  many  of  the  worm  infections  there 
is  eosinophilia.  The  fceces  should  be  examined  for  the  eggs  of  the 
parasites. 


164  CHLOEOSIS 

3.  Anaemia  from  Malignant  Disease. — The  type  of  anaemia  is  often 
chlorotic.  Malignant  disease  is  not  very  common  in  young  girls  without 
causing  symptoms  or  physical  signs,  but  may  occur.  Nucleated  red  cells 
are  more  common  and  more  numerous  in  malignant  disease  than  in 
chlorosis,  and  in  the  former  there  is  likely  to  be  some  degree  of  leucocy- 
tosis,  while  in  the  latter  the  leucopenia  and  high  lymphocyte  percentage 
will  be  distinguishing  features.  The  colour  index  is  rarely  so  low  in 
malignant  disease  as  in  chlorosis.  The  difficulty  may  only  be  cleared  up 
by  the  result  of  treatment. 

4.  Anosmia  from  Chronic  Concealed  Hcemorrhage. — The  bleeding  may 
be  from  piles,  and  patients  may  not  know  of  these  or  may  not  mention 
their  existence  without  a  direct  question.  More  commonly  the  bleeding 
is  from  a  gastric  or  duodenal  ulcer,  and  the  blood  is  so  altered  that  the 
patient  does  not  recognise  it.  The  diagnosis  here  may  be  difficult.  The 
red  cell  count  is  likely  to  be  lower  in  the  case  of  ulcer,  the  colour  index 
higher,  and  from  time  to  time  a  post-haemorrhagic  leucocytosis  may  be 
present.     The  stools  should  be  subjected  to  the  benzidine  test  for  blood. 

5.  Tuberculosis. — Cases  of  early  phthisis  and  other  forms  of  tuber- 
culosis not  infrequently  present  symptoms  and  a  general  appearance 
which  can  very  readily  be  mistaken  for  chlorosis.  Error  frequently 
does  arise  simply  because  chlorosis  is  taken  for  granted  and  the  lungs 
and  other  organs  are  not  examined  with  sufficient  care.  In  difficult 
cases  the  examination  of  the  blood  may  help,  but  the  character  of  the 
anaemia  tends  to  be  pretty  much  the  same,  and  the  leucocytes  undergo 
the  same  change  in  the  two  conditions.  The  low  colour  index  of 
chlorosis  is  the  chief  distinguishing  point.  It  is,  of  course,  to  be  borne 
in  mind  that  chlorotic  girls  may  become  infected  with  tuberculosis. 

The  temperature  does  not  give  much  help,  since  it  is  not  always 
raised  in  early  tuberculosis,  and  it  is  sometimes  (if  rarely)  raised  in 
cases  of  chlorosis.  One  or  other  of  the  tuberculin  tests  may  have  to  be 
employed  in  order  to  clear  up  the  diagnosis. 

6.  Kidney  Disease. — Chronic  nephritis  always  causes  anaemia  in 
young  subjects.  The  history  and  a  careful  examination  of  the  urine 
distinguish  the  two  conditions. 

7.  Pregnancy. — Early  pregnancy  should  be  borne  in  mind  as  a  cause 
of  anaemia  and  amenorrhcea. 

Treatment. — 1.  Prophylactic. — The  prophylaxis  of  chlorosis  largely 
resolves  itself  into  the  application  of  hygienic  principles  to  girls  of  the 
chlorotic  age.      In  families   where  the  mother  or   elder  sisters   have 


CHLOEOSIS  165 

suffered  from  chlorosis,  special  care  should  be  exercised  in  the  case 
of  the  younger  sisters.  Sufficient  and  not  excessive  exercise,  plenty  of 
fresh  air  and  good  food,  are  the  important  considerations.  A  timeous 
holiday  and  change  of  air  may  forestall  several  weeks  of  indifferent 
health.  The  administration  of  iron  as  a  prophylactic  measure  is  prob- 
ably worse  than  useless.  It  is  of  no  advantage  to  a  healthy  girl  to  take 
iron,  and  if  her  tissues  are  habituated  to  it,  it  may  fail  to  do  good  when 
it  is  required. 

2.  General. — Sunlight  and  fresh  air  are  essential.  Eest  is  also  a 
factor  of  the  greatest  importance,  even  in  the  comparatively  rare  cases 
where  deficient  exercise  may  have  had  a  causal  effect.  All  severe  cases 
should  be  kept  in  bed,  and  where  circumstances  permit,  even  cases  of 
moderate  severity  are  better  treated  in  bed  than  out  of  it.  To  be  more 
explicit,  it  may  be  stated  that  all  cases  with  a  percentage  of  haemoglobin 
less  than  60  should  be  kept  in  bed.  The  strain  on  the  heart  is  at  once 
relieved,  and  the  symptoms  of  dyspnoea,  faintness,  headache  and  neuralgia 
very  speedily  disappear.  They  just  as  readily  return,  however,  so  that 
it  may  be  well  to  inform  patients  at  once  that  they  are  to  be  kept  in 
bed  for  three  weeks.  This  period  may  be  curtailed  or  extended  as  the 
blood  examination  indicates,  but  will  be  found  a  fairly  satisfactory  aver- 
age. In  most  cases  it  will  be  some  weeks  longer  before  the  girl  is 
thoroughly  fit  to  return  to  work,  but  unfortunately  advice  to  this  effect 
is  too  often  disregarded.  In  the  less  severe  cases,  and  in  the  convales- 
cent stage  in  the  more  severe  cases,  patients  should  avoid  fatigue  and 
excitement  and  keep  early  hours.  When  the  patient  has  no  work  to  do, 
a  walk  in  the  open  air,  short  of  fatigue,  should  be  insisted  upon.  The 
more  active  forms  of  exercise  and  games  should  be  interdicted.  Cold 
bathing  should  be  avoided. 

Eegularity  of  meal  times  must  be  insisted  upon,  and  a  special  diet 
may  have  to  be  arranged.  Sometimes  the  craving  for  special  and  often 
unsuitable  articles  of  diet  and  the  habit  of  eating  between  meals  may  be 
best  overcome  by  ordering  relatively  small  meals  at  a  shorter  interval 
than  usual,  say,  every  three  hours.  The  chief  consideration  is  to  get  the 
patient  to  ingest  a  sufficient  quantity  of  protein,  and  some  firmness  may 
be  required  in  order  to  overcome  the  almost  invariable  dislike  for  meat 
which  chlorotics  evince.  A  small  but  increasing  quantity  may  have  to 
be  definitely  ordered  at  first.  When  gastric  disturbance  prevents  the 
taking  of  solid  food,  milk,  with  the  addition  of  an  equal  quantity  of 
cream,  may  be  advised.  This  prescription,  however,  requires  super- 
vision, as  the  milk  diminishes  the  appetite  for  other  kinds  of  food  and 


166  CHLOEOSIS 

the  total  amount  of  food  taken  may  be  insufficient.  In  the  case  of  fat 
patients  and  those  with  a  good  appetite  for  solid  food,  a  large  amount 
of  milk  should  not  be  given.  A  little  alcohol,  which  stimulates  the 
appetite  and  favours  fat  formation,  may  be  given  to  thin  patients.  The 
bowels  must  be  carefully  regulated.  Iron  has  a  slight  tendency  to  cause 
constipation,  and  chronic  constipation  is  very  common  in  girls  of  ehlorotic 
age.  Cascara  or  aloin  are  among  the  most  serviceable  drugs  in  this  con- 
nection. The  aloes  and  iron  pill  is  very  useful,  given  at  night  in  sufficient 
dose  to  secure  a  proper  action,  while  at  the  same  time  Blaud  is  being 
taken  after  meals.  In  some  cases  a  bitter  tonic  before  food,  or  gastric 
sedatives  such  as  bismuth  or  soda,  may  be  required  as  a  preliminary 
measure,  especially  if  the  stomach  is  sensitive  to  the  administration 
of  iron. 

3.  Special. — "Whatever  view  may  be  taken  of  the  pathology  of  the 
disease,  there  is  no  doubt  that  iron  cures  chlorosis  in  the  great  majority 
of  cases,  and  that  no  other  drug  has  even  approximately  the  same 
beneficial  effect. 

It  is  to  be  noted  that  iron  does  not  cure  chlorosis  by  replacing  iron 
lost  or  diminished  in  the  blood.  There  is  an  ample  supply  of  iron  for 
this  purpose  in  the  protein  constituents  of  the  food,  but  good  food  and 
rest  alone  will  not  cure  chlorosis. 

All  preparations  of  iron,  whether  organic  or  inorganic,  are  trans- 
formed in  the  stomach  into  ferric  chloride.  There  is  no  doubt,  however, 
that  the  inorganic  salts  are  much  more  efficacious  than  the  organic  in 
bringing  about  a  speedy  cure. 

Owing  to  a  mistaken  notion  that  inorganic  iron  is  not  absorbed, 
numerous  preparations  of  organic  iron  have  been  placed  upon  the 
market.  These,  perhaps  on  account  of  their  similarity  to  the  food- 
iron,  are  not  nearly  so  useful  as  the  inorganic  salts.  Moreover,  some 
of  them  after  all  contain  so  small  a  proportion  of  iron  that  enormous 
doses  would  be  required  to  supply  the  15  to  20  grains  which  is  the 
minimum  amount  of  metallic  iron  which  should  constitute  the  daily 
dosage. 

The  organic  preparations  may  be  divided  roughly  into  two  classes 
— (1)  Those  which  consist  mainly  or  entirely  of  haemoglobin,  usually 
derived  from  ox  blood,  kept  in  solution  and  with  preservatives  added, 
or  dried.  (2)  Those  which  consist  of  iron  in  combination  with  some 
albuminate,  peptonate,  or  other  protein  derivative.  To  some  of  both 
of  these  varieties — it  is  needless  to  say  that  they  are  all  proprietary 
and  often  "  elegant "  preparations — strychnine,  arsenic,  etc.,  are  added 


CHLOEOSIS  167 

in  small  doses.  The  first  class  are  so  disappointing  that  we  have  long 
ceased  even  to  experiment  with  them.  Some  of  the  second  class  are 
more  useful,  as  they  do  contain  a  fair  amount  of  iron,  and  are  well  borne 
by  delicate  stomachs  and  intestines,  and  in  very  mild  cases  of  chlorosis 
they  are  occasionally  useful.  Good  results  have  been  published  with 
them,  but  we  have  never  been  similarly  fortunate.  In  a  recent  case 
of  very  severe  chlorosis  (reds,  3,000,000  ;  haemoglobin,  28  per  cent.)  we 
gave  one  of  these  preparations  in  full  doses  for  a  fortnight.  The 
patient's  general  condition  did  not  improve,  though  she  was  kept  in 
bed  all  the  time,  and  the  count  and  haemoglobin  at  the  end  of  the 
fortnight  were  the  same.  Blaud's  pill  was  then  given,  and  at  the 
end  of  the  next  fortnight  the  reds  were  4,200,000,  haemoglobin  63 
per  cent. 

The  only  condition  in  which  the  organic  preparations  of  iron  appear 
to  have  a  special  application  is  in  those  rare  cases  in  which  we  fail  to 
find  an  inorganic  salt  which  the  stomach  will  tolerate.  They  are  useful 
also  in  secondary  anaemias  from  chronic  intestinal  catarrh,  and  in  such 
conditions  as  mucous  colitis. 

Of  the  inorganic  salts  of  iron  the  one  which  is  most  used  and  which 
is  probably  about  the  best  is  the  carbonate  in  the  form  of  Blaud's  pill 
or  the  saccharated  carbonate.  A  common  and  good  plan  is  to  give 
Blaud's  pill  as  a  capsule,  of  two  or  three  pills  strength.  It  is  not 
astringent,  and  is  generally  well  borne.  Eeduced  iron  is  very  useful, 
and  its  small  dose  is  an  advantage.  It  should  be  obtained  free  from 
sulphur  as  an  impurity,  otherwise  unpleasant  eructations  of  sulphuretted 
hydrogen  may  result. 

The  sulphate  and  perchloride  of  iron  are  astringent,  and  are  not  well 
tolerated  by  patients  with  irritable  stomachs,  but  when  they  can  be 
taken  very  satisfactory  results  may  be  obtained.  The  scale  preparations 
are  usually  easily  taken.  Their  disadvantage  is  the  small  proportion 
of  iron  they  contain.  The  dosage  is  important,  and  should  be  carefully 
regulated.  The  common  error  is  that  too  little  iron  is  taken.  The 
equivalent  of  two  Blaud's  pills  three  times  a  day  after  food  should 
be  prescribed  to  begin  with.  As  long  as  there  is  no  gastric  disturb- 
ance one  pill  may  be  added  every  second  day  till  from  twenty  to 
twenty-four  per  day  are  being  taken.  The  maximum  should  then 
be  persevered  with  for  some  weeks,  and  then  gradually  diminished 
before  being  left  off.  The  effect  of  the  iron  should  be  noted  by 
repeated  examination  of  the  blood.  As  long  as  the  percentage  of 
haemoglobin  continues  to  rise  the  iron  may  be  continued.     If  it  becomes 


168  CHLOROSIS 

stationary  before  the  normal  90  per  cent,  is  reached  it  is  better  to  leave 
off  iron  for  a  few  weeks  and  then  begin  again  with  the  smaller  doses. 
Generally  speaking,  we  find  it  well  to  give  iron  for  two  months  at  first, 
then  stop  for  three  weeks,  then  give  it  for  six  weeks,  and  so  on.  If  it 
is  given  uninterruptedly  for  long  periods  the  system  seems  to  get 
used  to  it  and  it  ceases  to  do  good.  The  iron  should  always  be  taken 
regularly  and  without  interruption.  Even  when  dyspeptic  symptoms 
are  complained  of  the  iron  should  not  be  too  readily  withdrawn  or 
diminished.  The  dyspepsia  is  more  likely  to  be  due  to  the  chlorosis 
than  to  the  iron.  It  is  often  found  that  patients  who  believe  they 
cannot  take  iron  can  do  so  without  difficulty  if  they  are  confined  to 
bed. 

In  cases  where  iron  disagrees  in  spite  of  changes  and  mild  gastric 
sedatives,  chalybeate  waters  may  be  tried.  When  iron  is  well  borne 
but  fails  to  do  good  it  may  be  combined  with  or  replaced  by  arsenic. 
The  latter  is  likely  to  succeed  best  in  cases  where  the  red  corpuscles 
are  considerably  diminished.  It  should  be  given  in  initial  small  doses 
and  gradually  increased.  Occasionally  a  few  doses  of  digitalis  seem 
to  initiate  improvement  after  iron  alone  has  falied. 

It  may  be  well  to  point  out  that  many  preparations  of  iron 
particularly  in  the  form  of  pills,  are  quite  useless. 

Some  cases  have  been  recorded  in  which  bleeding  has  been  resorted 
to  with  a  view  of  stimulating  the  bone-marrow,  and  a  certain  measure 
of  success  seems  to  have  followed  this  procedure.  The  amount  with- 
drawn is  about  4  ozs.  Measures  directed  towards  the  withdrawal  of 
fluid  from  the  body  by  dry  diet,  sweating,  and  free  purgation  do  not 
cure  the  disease,  and  do  not  appear  to  shorten  the  period  of  cure  by 
means  of  iron. 

The  standard  by  which  a  cure  is  to  be  determined  is  the  condition 
of  the  blood  and  not  merely,  the  appearance  of  the  patient. 


CHAPTEE  XVI 

SECONDARY  ANEMIA— SYMPTOMATIC   ANEMIA 

Anaemia  may  arise  from  a  very  large  number  of  causes.  Symptomatic 
anaemia  may  be  divided  into — 1.  Acute  post-haemorrhagic  anaemia,  and 
2.  Simple  secondary  anaemia. 

1.  Acute  Post-Ksmorrhagic  Anaemia 

Causes. — Haemorrhage  may  take  place — 

(a)  From  wounds  in  any  part  of  the  body ; 

(b)  From  rupture  of  vessels,  aneurysm,  or  varicose  veins  ; 

(c)  From  gastric  or  duodenal  ulcer,  oesophageal  or  gastric  veins  in 
cirrhosis  of  the  liver,  haemorrhoids,  typhoid  ulcers ; 

(d)  From  various  parts  of  the  body  in  the  bleeding  diseases,  haemo- 
philia, purpura,  scurvy,  pernicious  and  other  anaemias  and  leuco- 
cy  thaemia ; 

(e)  From  the  nose  or  respiratory  tract ; 
(/)  From  the  urinary  passages  ; 

(g)  From  tubal  abortion,  and  a  variety  of  uterine  conditions. 

Symptoms. — An  early  sign  is  pallor  of  the  skin,  lips,  and  conjunctivae. 
This  pallor  is  seen  before  the  loss  of  blood  is  very  great,  and  is  accounted 
for  in  part  by  psychical  conditions.  No  other  condition  occasions  so 
much  anxiety,  and  there  may  be  great  weakness,  giddiness,  and  faint- 
ness,  subjective  sensations  of  smell,  sound,  or  flashes  of  light,  or  even 
blindness.  There  are  cold  sweats  and  an  increased  secretion  of  urine. 
Palpitation  is  noticed,  and  is  followed  by  weakness  of  the  heart  and 
feebleness  of  the  sounds. 

The  pulse  changes  rapidly  in  volume  and  tension  and  soon  becomes 
somewhat  irregular,  and  the  pressure  is  low  and  volume  small.  Faint- 
ing is  often  seen  at  this  stage. 

Ptespirations  become  superficial,  and  sighing  is  frequent.  There 
may  be  hiccough,  nausea,  and  even  vomiting.  Symptoms  become  more 
severe  owing  to  loss  of  fluid.     Sweating  stops,  the  skin  becomes  dry, 

169 


v 


170     SECONDARY  ANAEMIA— SYMPTOMATIC  ANAEMIA 

the  eyes  dull.  Syncope  becomes  more  persistent.  In  the  conscious 
intervals  there  may  be  aphasia  or  paraphasia ;  the  voice  is  weak. 
Fibrillary  tremors  may  be  seen,  and  delirium  and  convulsions  may 
follow. 

If  the  haemorrhage  is  checked  before  a  fatal  result  takes  place  the 
patient  is  not  yet  out  of  danger.  The  blood  is  diluted  by  fluid  from 
the  tissues,  and  it  is  probable  that  the  hydraemia  leads  to  a  destruction 
of  some  of  the  less  resistant  corpuscles. 

The  Blood  Changes. — As  blood  is  lost  coagulability  increases,  so 
that  at  the  end  of  a  big  haemorrhage  clotting  may  be  almost  immediate. 
Whenever  blood  is  lost  to  any  appreciable  extent  the  body  fluids  pass 
into  the  plasma,  so  that  the  blood  is  diluted.  In  severe  cases  the  red 
cell  count  may  fall  almost  at  once  to  less  than  one  million  per  c.mm. 
Haemoglobin  is  of  course  reduced  proportionately  until  regeneration 
begins.  The  maximum  degree  of  anaemia  is  generally  not  reached  till 
from  one  to  three  days,  or  even  longer,  after  the  bleeding.  If  the 
haemorrhage  be  survived  regeneration  begins  almost  at  once.  Young 
red  cells,  poor  in  haemoglobin,  are  passed  out  from  the  bone-marrow,  so 
that  the  colour  index  falls,  it  may  be  as  low  as  05.  The  red  corpuscles 
are  small,  and  show  great  inequality  in  size  and  a  moderate  amount  of 
distortion.  There  is  very  marked  polychromasia,  and  a  small  number 
of  the  corpuscles  may  show  punctate  basophilia.  On  the  second 
or  third  day  nucleated  red  cells  appear.  These  are  normoblasts  ex- 
clusively in  most  cases,  but  if  there  has  been  great  marrow  disturbance 
a  few  megaloblasts  may  also  be  found.  Occasionally  after  haemor- 
rhage sudden  accessions  of  normoblasts  to  the  circulation  (blood  crises) 
occur. 

White  Cells.  —  Immediately  after  haemorrhage  an  increase  of  the 
polymorphs  in  the  circulating  blood  takes  place.  The  leucocytosis  is 
not  very  large,  and  after  a  single  haemorrhage  it  is  of  short  duration, 
often  disappearing  within  eight  hours,  though  it  may  persist  for  three 
or  four  days.  After  a  large  haemorrhage  the  blood-plates  are  always 
increased.  The  blood  examination  may  throw  light  on  symptoms 
otherwise  obscure,  as  in  the  case  of  ruptured  aneurysm  or  ruptured 
ectopic  gestation,  or  internal  haemorrhage  after  injury. 

Course  and  Prognosis. — As  already  indicated,  the  maximum  severity 
of  the  anaemia  is  not  reached  till  some  days  after  the  actual  haemorrhage. 
It   is  quite  impossible  to  say  to  what  extent  haemorrhage  may  occur 


SECONDARY  ANAEMIA— SYMPTOMATIC   ANAEMIA     171 

without  being  fatal.  Its  suddenness,  the  age  and  strength  of  the 
patient,  are  important  varying  factors.  We  had  one  case  of  haema- 
temesis  in  which  the  red  corpuscles  fell  to  400,000  per  c.mm.  in  two 
days,  and  recovery  followed. 

The  rate  of  regeneration  will  depend  on  the  extent  of  the  blood 
loss  and  the  age  and  nutrition  of  the  patient.  A  moderate  haemor- 
rhage in  a  young  healthy  adult  will  be  made  good  in  a  few  days. 
After  most  surgical  operations  in  comparatively  healthy  persons  there 
is  no  anaemia  after  ten  days. 

After  very  severe  or  repeated  haemorrhage  regeneration  will  require 
a  month  or  six  weeks,  but  this  would  be  a  modest  estimate  for  weakly 
or  elderly  patients  or  cases  in  whom  some  degree  of  bone-marrow 
exhaustion  had  supervened.  Infants  and  young  children  bear  haemor- 
rhage badly,  but  in  cases  which  survive,  regeneration  is  particularly 
rapid  after  the  first  few  days. 

Treatment. — The  first  indication  is,  of  course,  to  arrest  the  haemor- 
rhage by  appropriate  measures.  The  symptoms  may  then  be  met  by 
lowering  the  head,  slaking  the  thirst,  and  making  the  patient  as  com- 
fortable as  possible.  If  the  haemorrhage  has  been  definitely  arrested 
a  stimulant  will  do  good,  and  will  be  most  grateful  to  the  patient.  It 
must  be  withheld,  however,  unless  death  is  threatening,  in  cases  where 
there  is  risk  of  a  return  of  the  bleeding. 

Severe  symptoms  due  to  loss  of  fluid  may  be  met  by  bandaging  the 
patient's  limbs,  by  transfusion  of  blood  or  of  physiological  saline  solu- 
tion. It  is  doubtful  if  transfusion  of  blood  has  any  advantage  over 
saline  transfusion,  and  the  latter,  being  more  simple,  is  to  be  preferred. 

Injections  into  the  rectum  may  be  retained  and  absorbed  and  some- 
times suffice,  but  in  more  urgent  cases  the  transfusion  must  be  into  a 
vein.  Injections  are  sometimes  made  into  the  loose  fibrous  tissue  of  the 
axilla  or  elsewhere,  but  are  painful  and  probably  not  so  efficacious  as 
the  intravenous  method. 

The  after-treatment  consists  of  confinement  to  bed,  careful  dieting, 
since  the  stomach  is  often  very  irritable  for  several  days  or  even  weeks, 
such  symptomatic  measures  as  may  be  indicated,  and  the  administra- 
tion of  iron  on  the  lines  suggested  in  the  case  of  chlorosis  (Chap.  XV.). 

2.  Simple  Secondaky  Anemia 
Causes. — The  causes  of  secondary  anaemia  are  very  numerous,  and 
may  be  grouped  as  follows : — 


172     SECONDAEY  ANEMIA— SYMPTOMATIC  ANEMIA 

(1)  Eepeated  haemorrhage. 

(2)  Active  haemolysis,  from  such  conditions  as  cholsemia,  severe 
sepsis,  and  malaria. 

(3)  Disturbance  of  the  balance  between  production  and  elimination 
of  red  corpuscles.  The  lives  of  the  red  corpuscles  may  be  shortened 
by  a  variety  of  adverse  conditions,  and  the  same  conditions  affecting 
the  marrow  may  lead  to  the  output  of  corpuscles  with  diminished 
resistance.     Among  these  conditions  are — 

(a)  Toxic     conditions,     e.g.     sepsis,     fevers,     syphilis,      malignant 

disease. 

(b)  Improper  nourishment  and  unfavourable  surroundings. 

(c)  Exhausting  disease  such  as   Bright's   disease,  chronic   catarrh 

of  the  alimentary  tract  and  consequent  loss  of  mucus  and 
epithelium,  lactorrhoea,  and  the  various  conditions  discussed 
in  Part  IV. 

Symptoms. — The  symptoms  are  often  largely  masked  by  those  of 
the  causal  condition.  In  an  uncomplicated  case  there  is  very  great  pallor. 
Patients  look  very  white  and  have  none  of  the  greenish  colour  of  chlorosis 
or  the  yellowish  tinge  of  pernicious  ansemia.  A  patient  suffering  from 
secondary  ansemia  with  two  million  corpuscles  per  c.mm.  always  looks 
far  more  anaemic  than  a  patient  suffering  from  pernicious  ansemia  with 
one  million. 

The  appetite  is  greatly  impaired  and  all  the  digestive  functions  are 
at  a  low  level.  Owing  to  deficient  oxidation  there  is  fatty  degeneration 
of  the  organs.  The  heart  acts  feebly,  its  rhythm  may  be  irregular, 
there  are  hsemic  murmurs.  Fainting  may  occur  with  sudden  changes 
in  posture ;  there  is  often  palpitation  and  dyspnoea  on  slight  exertion. 
The  blood-pressure  is  not  diminished,  unless  there  is  considerable  cardiac 
weakness. 

(Edema  about  the  ankles  may  occur,  probably  due  to  the  hydrsemia. 
There  is  sometimes  albuminuria.  Spontaneous  hsemorrhages,  chiefly  in 
the  form  of  petechise,  sometimes  occur,  but  are  not  common,  and  are 
possibly  accounted  for  by  fatty  change  in  the  vessels. 

Nervous  symptoms  may  develop.  Patients  are  often  querulous  or 
irritable.  Actual  lesions  have  been  found  post-mortem.  Among  these 
have  been  atrophy  of  ganglion  cells  and  deficient  staining  of  Nissl's 
granules. 

Blindness  occasionally  occurs,  clue  sometimes  to  no  discoverable 
lesion,  sometimes  to  actual  optic  neuritis. 


SECONDAKY  ANAEMIA— SYMPTOMATIC   ANAEMIA     173 

The  Blood  Changes. — The  chief  blood  changes  may  be  very  diverse 
according  to  the  nature  of  the  cause,  and  a  special  part  of  this  book  is 
devoted  to  a  description  of  them  from  the  etiological  standpoint.  The 
changes  common  to  all  and  representing  uncomplicated  anaemia  are 
similar  in  the  main  to  those  of  acute  hemorrhagic  amemia.  Poikilo- 
cytosis  is  likely  to  be  more  marked.  Nucleated  red  cells  are  less 
numerous,  unless  just  after  a  fresh  hemorrhage  in  a  case  of  not  too  long 
standing.  The  leucocyte  reaction  is  also  less.  In  chronic  hemorrhagic 
anemia  there  may  even  be  leucopenia.  In  a  long  standing  case  there 
may  be  a  few  myelocytes  in  the  circulating  blood. 

Significance  of  the  Blood  Changes. — The  diagnostic  value  of  blood 
examination  may  be  considerable.  Cases  of  weeping  aneurysm,  bleeding 
piles,  and  gastric  or  duodenal  ulcer  may  be  cited  as  examples,  and  treat- 
ment might  be  influenced  after  traumatic  or  other  hemorrhage  by  a 
knowledge  of  its  extent. 

The  blood  count  rather  than  the  symptoms  may  occasionally  give  a 
clue  to  the  diagnosis  of  many  cases  of  repeated  hemorrhage  ;  and  granted 
that  anemia  of  a  secondary  type  is  found,  careful  investigation  of 
possible  sources  of  hemorrhage  must  be  made. 

Among  causes  of  anemia  which  are  specially  common  and  fre- 
quently overlooked  are  bleeding  piles,  monorrhagia  or  metrorrhagia, 
duodenal  ulcer,  and  worm  infections. 

Treatment. — After  repeated  hemorrhages  the  reaction  on  the  part 
of  both  red  and  white  cells  is  not  so  brisk  as  after  a  single  hemorrhage, 
and  patients  who  become  anemic  from  such  causes  as  bleeding  piles, 
fibroids,  etc.,  may  require  careful  and  prolonged  treatment  before  the 
blood  returns  to  its  normal  condition. 

Mikulicz,  many  years  ago,  advanced  the  view  that  surgical  opera- 
tions should  not  be  undertaken  when  the  hemoglobin  percentage  is 
less  than  30.  This  is  probably  as  reasonable  a  general  law  as  can  be 
laid  down  in  medicine.  We  can  quote  one  case  where  hysterectomy 
for  bleeding  fibroids  was  performed  when  the  hemoglobin  percentage 
had  fallen  to  24.  The  patient  did  well.  In  another  case  of  the  same 
nature  hysterectomy  was  performed  when  the  red  cell  count  was 
2,000,000,  hemoglobin  30  per  cent.  In  a  fortnight  after  operation 
the  reel  corpuscles  numbered  2,900,000,  the  hemoglobin  amounted  to 
50  per  cent.  It  should  be  remembered  that  in  skilful  hands  hyster- 
ectomy is  practically  a  bloodless  operation.  In  chronic  gastric  and 
duodenal  ulcers  and  similar  conditions  with  slowly  advancing  anemia, 


174     SECOND  ABY   ANEMIA— SYMPTOMATIC  J  ANAEMIA 

surgical  aid,  to  be  of  service,  must  be  invoked  before  the  haemoglobin 
percentage  has  fallen  to  30  or  even  40. 

The  treatment  of  secondary  ansemia,  apart  from  the  treatment  of 
the  cause,  is  to  be  carried  out  on  the  lines  laid  down  in  the  treatment 
of  chlorosis  (Chap.  XV.). 


CHAPTER  XVII 

APLASTIC   ANEMIA 

This  condition  is  characterised  by  a  very  marked  reduction  of  red  cor- 
puscles and  an  absence  of  the  blood  changes  associated  with  regeneration 
in  the  bone-marrow. 

Etiology. — The  majority  of  the  cases  have  occurred  in  patients  under 
forty  years  of  age.  Under  twenty  and  over  forty  the  condition  is  much 
less  common.  In  the  majority  of  cases  there  is  no  discoverable  cause, 
but  the  condition  has  followed  bothriocephalus  infection,  pernicious 
anaemia,  syphilis,  albuminuria,  and  endometritis.  A  history  of  severe  or 
repeated  haemorrhages  is  common,  and  it  may  follow  severe  septic  and 
toxic  conditions. 

Pathology. — There  is  some  fatty  degeneration  and  the  usual  accom- 
paniments of  anaemia.  The  liver  and  spleen  sometimes  give  a  slight 
iron  reaction.  The  spleen  is  generally  fibrous,  the  Malpighian  corpuscles 
are  small,  and  cells  are  scanty  in  the  pulp.  The  lymphatic  glands 
contain  comparatively  few  free  cells.  The  bone-marrow,  even  in  the 
flat  bones,  is  pale.  The  marrow  in  the  shafts  of  the  long  bones  presents 
the  characters  of  ordinary  yellow  marrow,  except  in  some  instances  for 
a  few  small  scattered  red  islands. 

On  microscopic  examination  areas  of  marrow  may  show  gelatinous 
degeneration.  In  large  areas  there  may  be  nothing  but  fat  and  fibrous 
tissue,  but  in  the  red  islands  blood-cells  are  found ;  these  are  for  the 
most  part  lymphocytes.  A  few  red  cells  are  seen  in  scattered  areas ; 
among  them  are  normoblasts,  and,  in  some  cases,  a  good  many  megalo- 
blasts.  Many  of  them  show  karyorrhexis  and  other  indications  of 
degeneration.  There  is  sometimes  polyehromasia  and  basophilic 
stippling. 

Granular  cells  are  very  scanty  in  the  marrow,  but  islands  of  myelo- 
cytes may  be  found.  There  are  also  lymphoid  cells  showing  a  transition 
from  the  myeloblast  to  the  myelocyte.  Eosinophils  are  very  rare. 
Giant  cells  are  scanty  or  altogether  absent  in  sections.  Phagocytes  con- 
ns 


176  APLASTIC   ANAEMIA 

taining  red  cells  and  pigment  can  often  be  demonstrated.  A  remarkable 
increase  of  basophil  leucocytes  not  only  in  the  marrow  but  throughout 
the  fibrous  tissues  has  been  seen  in  a  few  cases. 

The  condition  appears  to  be  due  to  an  exhaustion  of  the  bone- 
<  marrow,  or  an  inability  to  respond  to  calls  upon  it.  We  have  seen  it 
in  several  instances  in  which  death  has  followed  repeated  or  continued 
haemorrhage.  It  also  follows  severe  septic  and  toxic  conditions.  In 
some  cases  the  aplasia  appears  to  be  due  to  the  severity  of  the  toxin,  so 
that  regeneration  never  takes  place.  In  other  cases  regeneration  may 
first  occur  and  then  fail.  In  the  cases  in  which  no  causal  condition 
can  be  discovered  there  may  be  an  inherent  vulnerability  or  weakness 
of  the  marrow  which  renders  it  unable  to  respond  to  even  a  slight  extra 
demand  upon  its  functions. 

Aplastic  ansemia  may  apparently  occur  as  a  last  stage  in  pernicious 
anaemia. 

Symptoms. — The  symptoms  are  those  usually  found  in  severe  ansemia, 
and  need  not  be  repeated.  In  many  cases  there  is  a  tendency  to 
haemorrhages  from  the  gums  and  mucous  membranes,  and  purpura 
is  often  seen.  There  is  no  special  tendency  for  any  enlargement  of 
the  liver,  spleen,  or  lymphatic  glands  to  take  place. 

Blood  Changes. — The  blood  looks  pale.  Eouleaux  formation  is 
deficient.  The  red  cells  are  greatly  diminished  in  number.  Counts 
under  one  million  are  fairly  frequent,  and  even  lower  counts  have  been 
noticed.  There  is  generally  a  diminution  in  the  average  size  of  the 
red  corpuscles.  Poikilocytosis  may  be  marked.  A  fair  number  of 
megalocytes  are  sometimes  present.  Polychromasia  is  generally  absent, 
and  is  never  very  marked.  Normoblasts  are  sometimes  noted  in  very 
small  numbers.  Megaloblasts  are  even  more  rare,  except  in  cases 
occurring  in  children.  Both  forms  of  nucleated  red  cells,  if  they  have 
been  present,  disappear  as  the  case  advances. 

The  colour  index  is  generally  rather  low,  but  in  a  few  cases  it  has 
been  over  1.  This  is  doubtless  due  to  a  certain  amount  of  megalo- 
blastic regeneration  in  parts  of  the  marrow,  so  that  megalocytes  are 
turned  out  into  the  circulation.  Too  much  stress,  however,  must  not 
be  laid  upon  observations  on  the  percentage  of  haemoglobin,  as  it  is 
very  difficult  indeed  to  make  accurate  estimations  when  ansemia  is 
extreme. 

It  is  extremely  difficult  to  make  a  certain  diagnosis  during  life 


APLASTIC   ANEMIA 


177 


between  aplastic  anaemia  with  a  high  colour  index  and  pernicious 
anaemia.  The  absence  or  disappearance  of  nucleated  reds  in  the  former 
case,  and  their  tendency  to  increase  in  the  latter  case  as  the  disease 
progresses,  is  usually  suggestive. 

The  number  of  leucocytes  is  almost  always  diminished,  and  certainly 
always  towards  the  close  of  the  case.  The  reduction  chiefly  affects  the 
cells  of  the  granular  series,  except  that  basophils  may  be  more  numerous 
than  usual.  Lymphocytes  are  always  present  in  high  percentages,  and 
are  often  the  most  numerous  white  cell  in  the  blood.  Blood-plates  are 
diminished  in  number. 

The  following  cases 1  may  be  quoted : — 


'o 

* 

03 

m 

03 

y. 

03 
CO 

ft 

s 

O 
t5 

T3 
U 

"o 

>> 

o 

o 
S 
>> 
"o 

o 
ft 

s 

ft 
o 
_c 

o 

ft 
o 

ci 

03 

>> 
O 

o 
>> 

M  s 

O   o 

.5  ft 

o 

CD 
03 

m 

< 

« 

O 

J 

FU 

A 

H 

m 

§ 

£ 

£ 

Steinhaus  and  Stordeur 

F. 

43 

2,000,000 

5,000 

25 

75 

0 

II                 !!               >1             •             • 

M. 

27 

1,060.000 

6-s 

2,700 

31 

69 

0 

'6 

Carslaw  and  Dunn 

M. 

24 

1,008,000 

10 

4,800 

19 

77 

0 

o" 

4 

24 

(late 

r) 

650,000 

1-1 

2,000 

16 

78 

0-5 

0-75 

5 

0 

Barberis          .... 

F. 

2,200,000 

0-6 

4,600 

0 

,, 

24 

330,000 

1-5 

1,600 

33 

67 

0 

o" 

0 

'6 

,, 

32 

1,600,000 

0-9 

5,600 

50 

49 

0 

0 

0 

0 

(late 

r) 

3S0,000 

1-3 

2,600 

77 

21 

1 

0 

0 

0 

F 

68 

1,200,000 

1-25 

4,000 

48 

51 

0 

1 

0 

»{ 

Very 
few. 

P.M.    no   increase   of  red 

marrow  in   femora,   ribs,   or 

,, 

1,300,000 

1-15 

3,200 

35 

62 

0 

3 

0 

0 

0 

sternum.    History  of  antemia 

,, 

,, 

1,700,000 

1-1 

10,000 

83 

13 

2 

0 

2 

0 

0 

only  three  weeks  before  ad- 

j, 

,, 

S00,000 

1-25 

4,400 

49 

51 

0 

0 

0 

0 

0 

mission.      In    hospital    ten 

,, 

900,000 

1-0 

8,000 

64 

34 

1 

1 

0 

0 

0 

days. 

Authors 

P. 

32 

625,000 

1-17 

2,200 

0 

0 

P.M.   no    increase    of   red 

,, 

,, 

560,000 

1-4 

1,200 

36 

63 

1 

o" 

0 

0 

0 

marrow.     History  of  slowly 

,, 

,, 

715,000 

1-23 

1,500 

0 

0 

progressive  anaemia  for  two 

,, 

,, 

980,000 

1-1 

2,600 

0 

0 

years.      In    hospital    seven 

,, 

,, 

550,000 

1-4 

3,700 

0 

0 

weeks. 

,, 

" 

330,d00 
340,000 

1-4 
1-4 

3,500 
3,600 

0 
0 

0 
0 

Authors 

M. 

19 

960,000 

o-s 

16,900 

70 

30 

0 

0 

0 

0 

0 

P.M.   no  increase  of  red 

,, 

720.000 

0-8 

12,000 

65 

34 

1 

0 

0 

0 

0 

marrow.      Haematemesis  for 

,, 

800,000 

0-75 

6,000 

0 

0 

fifteen    days    before    death ; 

quite    healthy    before.     Nu- 

merous   ulcerated   areas    in 

stomach. 

Diagnosis. — The  diagnosis  depends  upon  the  blood  examination,  but 
often  cannot  be  made  with  certainty  during  life. 


Prognosis. — In  many  cases  aplastic  anaemia  is  simply  the  terminal 
phase  of  a  serious  disease.     In  any  case  the  duration  of  the  condition 

1  For  cases  and  references,  see  Hirschfeld,  Folia  Hceviatologica,  xii.  1  Teil,  1911, 
p.  347. 

12 


178  APLASTIC   ANAEMIA 

never  exceeds  a  few  months.   It  may  terminate  suddenly  by  haemorrhage, 
or  be  cut  short  by  some  intercurrent  disease,  such  as  pneumonia. 

Treatment. — The  only  possible  chance  of  doing  good  would  be  the 
discovery  of  a  removable  cause,  but  even  then  treatment  would  be  late 
in  the  day.  In  all  ordinary  circumstances  we  have  to  deal  with  an 
exhausted  marrow,  and  until  an  elixir  of  life  is  discovered  curative 
treatment  is  out  of  the  question.  The  drugs  mentioned  in  connection 
with  secondary  and  pernicious  anaemia  might  be  tried. 


CHAPTER  XVIII 
SPLENIC  ANEMIA— PHAGOCYTIC   AKZEMIA 

Splenic  Anaemia  or  Banti's  Disease 

This  is  a  disease  of  unknown  causation,  characterised  by  enlargement 
of  the  spleen,  anaemia  with  special  blood  changes,  in  the  later  stages 
by  cirrhosis  of  the  liver  with  jaundice,  and  by  an  exceedingly  chronic 
course. 

Morbid  Anatomy  and  Pathology. — The  naked-eye  changes  are  those 
associated  with  cirrhosis  of  the  liver  and  spleen,  and  jaundice. 

Spleen. — The  capsule  is  enormously  thickened.  There  is  a  great 
increase  of  fibrous  tissue  throughout  the  organ.  The  Malpighian  bodies 
are  atrophied.  White  cells  in  the  pulp  are  scanty,  and  lymphocytes 
predominate.  There  is  often  a  large  quantity  of  pigment  either  in  large 
cells  or  lying  free  in  the  pulp,  and  a  large  proportion  of  this  gives  the 
free  iron  reaction.  The  arteries  are  sclerosed  and  the  sinuses  are 
dilated  and  engorged  with  blood. 

Liver. — The  portal  spaces  show  a  great  increase  of  fibrous  tissue. 
The  fibrous  tissue  may  spread  into  the  liver  substance  so  that  the 
lobular  arrangement  may  be  destroyed  and  small  groups  of  cells 
may  be  cut  off  and  strangulated.  The  fibrous  tissue  strands  show 
considerable  infiltration  with  leucocytes.  Pigment  may  be  found 
in  the  capillaries  and  in  the  endothelial  cells.  Pigment  is  scanty  or 
absent  in  the  liver  cells.  Some  of  it,  when  present,  gives  the  free 
iron  reaction. 

Bone-Marrow. — There  is  usually  a  certain  amount  of  erythroblastic 
reaction  and  some  extension  of  red  marrow  into  the  shaft  of  the  long 
bones.  Normoblasts  are  slightly  more  numerous  than  usual,  and  a 
few  megaloblasts  may  be  seen.  Unless  there  has  been  some  complica- 
tion there  is  but  slight  leucocytic  activity,  and  the  majority  of  the 
white  cells  are  lymphocytes.  Giant  cells  are  often  scanty,  and  are 
always  small  and  degenerated.  Some  iron  pigment  is  commonly  found 
in  the  leucocytes  and  endothelial  cells. 


180  SPLENIC   ANiEMIA— PHAGOCYTIC   ANEMIA 

Kidneys. — A  varying  degree  of  cirrhotic  change  has  been  present  in 
all  our  cases. 

The  pathology  of  the  disease  is  not  understood.  It  has  been 
suggested  that  it  is  due  to  some  toxin  absorbed  from  the  intestine. 
Mitchell  Clarke  suggests  the  view  that  it  is  due  to  a  failure  of  the 
eliminative  function  of  the  spleen,  whereby  dead  blood  corpuscles  and 
their  products  are  allowed  to  pass  through  the  spleen  and  set  up 
irritation  there  and  later  in  the  liver.  These  views  fail  to  explain 
the  improvement  that  occurs  in  cases  in  which  the  spleen  has  been 
successfully  removed.  It  is  more  probable,  as  Eolleston  suggests, 
that  there  is  a  chronic  infective  or  toxic  process  located  in  the 
spleen. 

Sutherland  and  Burghard1  suggest  that  it  is  due  to  loss  of  vaso- 
motor control  of  the  splenic  artery,  which  would  account  for  the 
splenic  hyperplasia  and  consequent  exaggeration  of  its  function  of 
removing  effete  blood  corpuscles.  The  increased  flow  of  blood 
through  the  splenic  artery  would  lead  to  distension  of  the  arteries 
of  the  stomach  and  occasional  rupture  of  vessels  and  hsematemesis. 

Symptoms. — The  disease  affects  young  adults,  and  is  most  common 
about  the  age  of  thirty.  The  disease  has  occurred  in  more  than  one 
member  of  the  same  family,  and  a  variety  of  conditions  such  as 
malaria  have  preceded  it,  but  none  of  these  antecedent  circumstances. 
are  sufficiently  constant  to  suggest  a  causal  relationship. 

First  Stage. — At  the  outset  there  may  be  no  symptom  beyond  -the 
mere  presence  of  an  enlarged  spleen.  Attention  may  be  drawn  to  this 
by  pain  set  up  by  perisplenitis;  more  commonly  the  enlargement  is 
discovered  more  or  less  by  accident.  Occasionally  some  weakness 
or  dyspepsia  may  be  complained  of.  In  one  case  in  this  stage  a 
very  remarkable  leucopenia  was  present,  although  there  were  no 
symptoms  of  anaemia,  and  the  red  cells  looked  healthy. 

Second  Stage. — It  is  usually  in  this  stage  that  the  condition  is  first 
observed.  The  splenic  enlargement  is  now  considerable,  and  the  spleen 
may  reach  below  the  umbilicus.  Anaemia  with  the  usual  symptoms 
may  become  a  marked  feature.  Gastro-intestinal  disturbance,  with 
sickness  and  diarrhoea,  may  become  prominent.  Haemorrhages  occur 
in  a  large  proportion  of  the  cases.  These  are  most  commonly  associated 
with  the  alimentary  canal,  but  epistaxis  and  purpura  have  been  noted 
with  some  frequency. 

1  Lancet,  24th  December  1910. 


SPLENIC   ANAEMIA— PHAGOCYTIC   ANEMIA  181 

Third  Stage. — The  symptoms  of  cirrhosis  of  the  liver  now  become 
added  to  the  existing  anemia.  The  liver,  and  to  a  less  extent  the 
spleen,  tend  to  diminish  in  size.  Gastro-intestinal  symptoms  become 
marked.  Vomiting  and  haematemesis  are  common.  Jaundice  is  present 
in  varying  degree.  Ascites  becomes  a  prominent  symptom.  The  ten- 
dency to  haemorrhages  increases,  the  anaemia  advances,  the  leucocytes 
diminish,  and  there  is  great  weakness  and  prostration.  Death  is 
brought  about  by  a  large  haemorrhage,  or  by  toxaemia  or  exhaustion, 
or  some  intercurrent  complication. 

Blood  Changes. — In  the  first  stage  leucopenia  may  be  the  only 
alteration  in  the  blood.  In  the  second  stage  the  red  corpuscles 
commonly  number  two  and  a  half  or  three  millions.  Haemoglobin 
is  reduced  rather  more  than  proportionately,  so  that  the  colour  index 
is  low.  The  index,  however,  seldom  reaches  the  very  low  figure 
sometimes  noticed  in  chlorosis.  In  a  few  cases  poverty  of  haemoglobin 
has  been  the  only  blood  change.  There  may  be  some  deformity  and 
alteration  in  size  of  the  red  cells.  Normoblasts  have  been  found  in 
a  majority  of  the  cases,  and  in  a  few  instances  megaloblasts  appear. 
Polychromasia  and  granular  degeneration  were  a  marked  feature  in 
one  of  our  cases. 

The  white  cells  are  never  increased,  and  in  the  great  majority  of  cases 
are  diminished  in  number.  The  diminution  may  be  present  at  an  early 
stage,  and  becomes  more  marked  as  the  disease  proceeds.  The  number 
per  cubic  millimetre  may  be  500  or  even  less.  In  the  second  stage  all 
varieties  seem  to  be  affected,  so  that  differential  counts  are  not  much 
disturbed.  In  the  late  stages  lymphocytes  are  more  affected,  and  still 
later  the  eosinophils  tend  to  disappear. 

In  one  case  we  found — 

Date  Tied  Cells  Hh     White  Cells       Poly"        Lymplio-        Eosino-       Baso-        Myelo- 

uate.  Keauem.  ud.    wiaite  oens.    morphs_       cytes_  pllils_         phils,        cytes_ 

17/3/04         3,848,000          74         2600           57            40              111 
11/5/04         1,840,000  40  800  94  6  

The  glycogen  reaction  in  this  case  was  well  marked. 

The  blood  changes  often  admirably  reflect  the  extremely  chronic 
character  of  the  disease,  and  cases  have  been  seen  and  recorded  in  which 
the  blood-picture  remained  practically  unchanged  after  an  interval  of 
five  years. 

In  those  cases  in  which  splenectomy  has  been  successfully  performed 
the  blood  has  shown  those  changes  which  have  followed  splenectomy 
for  such  conditions  as  trauma. 


182  SPLENIC   ANEMIA— PHAGOCYTIC   ANAEMIA 

Diagnosis. — In  the  first  stage  it  may  be  impossible  to  make  a 
definite  diagnosis.  If  there  be  leukopenia  along  with  the  splenic 
enlargement,  and  if  infection  by  animal  parasites  can  be  excluded, 
splenic  anaemia  is  the  most  probable  diagnosis.  Pallor,  jaundice  and 
ascites,  greater  anaemia  and  more  generalised  haemorrhages,  a  smaller 
size  of  liver  and  spleen,  and  a  relatively  more  acute  course,  distinguished 
Banti's  disease  from  Gaucher's  splenomegaly.  The  disease  differs  from 
the  splenic  anaemia  of  infants,  which  is  always  associated  with  leucocy- 
tosis  (see  Chap.  XXVII.).  The  splenic  enlargement,  the  blood  changes, 
and  the  chronic  course  distinguish  the  second  stage.  The  third 
stage  can  be  distinguished  from  primary  hepatic  cirrhosis  by  the 
blood  changes,  and  by  haemorrhages  not  specially  associated  with  the 
portal  circulation, 

Prognosis. — In  a  very  few  cases  spontaneous  cure  seems  to  have 
occurred.  Much  more  commonly  the  disease  is  gradually  progressive,  but 
there  may  be  sudden  exacerbations  and  prolonged  remissions.  The  risk 
of  intercurrent  affections  is  the  greatest  danger.  Sudden  haemorrhages 
may  occur  at  any  time,  but  are  more  common  in  the  later  stages.  At 
the  best  the  patient  cannot  look  forward  to  anything  better  than  a  life 
of  semi-invalidism  unless  a  successful  splenectomy  is  performed.  It 
has  to  be  remembered  that  in  a  few  cases  symptoms  have  persisted 
after  the  spleen  has  been  removed. 

Treatment. — The  diet  should  be  bland  and  unirritating.  In  large 
measure  the  medicinal  treatment  must  be  symptomatic.  Benefit  has 
been  found  to  follow  the  use  of  arsenic  and  of  quinine.  Boric  acid 
has  been  advocated  by  Bramwell.  X-rays  applied  to  the  spleen  has 
caused  a  return  to  normal  in  its  size  and  in  the  blood  condition  in 
some  cases.  In  others  there  is  improvement  up  to  a  certain  point 
without  further  benefit.  In  yet  other  cases  X-rays  have  done  no  good 
at  all. 

A  sufficiently  large  number  of  successful  cases  has  been  recorded 
to  justify  the  removal  of  the  spleen  in  cases  which  are  not  improving 
under  medicinal  treatment.  The  operation,  however,  is  not  to  be  lightly 
recommended.  In  a  few  cases  it  has  been  immediately  fatal  from 
haemorrhage ;  in  others  there  has  been  fatal  gastro-intestinal  haemor- 
rhage after  a  few  days.  The  danger  from  haemorrhage  increases  with 
increasing  anaemia.  Death  from  pneumonia  followed  operation  in  one 
of  our  cases,  and  a  fatal  result  has  followed  vague  gastro-intestinal 
symptoms  some  months  after  the  operation. 


SPLENIC   ANAEMIA— PHAGOCYTIC   ANEMIA  183 


LITERATURE 

Paulicek,  Folia  Hcematologica,  ix.  1  Teil,  1910,  475.     Banti,  Folia  Hcemato- 
logica,  x.  1  Teil,  1910,  1. 


Primary  Splenomegaly:  Gaucher's  Disease 

This  condition  closely  resembles  Banti's  disease  as  regards  symptoms 
and  course.  It  often  affects  several  members  of  a  family.  Hereditary 
influence  is  not  so  common,  but  cases  occurring  in  father  and 
daughter  and  in  mother  and  daughter  have  been  recorded.  The  age 
incidence  is  earlier  than  in  Banti's  disease,  and  it  is  more  common 
in  females. 

Pathology. — The  spleen  is  uniformly  enlarged,  and  sections  have 
a  grey  appearance  with  scattered  white  patches.  Malpighian  bodies 
are  small.  The  pulp  shows  a  great  infiltration  with  large  hyaline 
cells  measuring  20  to  40  /*  in  diameter,  with  small  nuclei,  apparently 
endothelial  in  their  nature  and  probably  derived  from  the  reticulum. 
Some  of  the  infiltrated  areas  show  necrotic  changes.  Their  distribution 
suggests  an  alveolar  arrangement.  The  liver  is  also  enlarged,  and  in 
its  fibrous  tissue  are  groups  of  cells  resembling  those  found  in  the 
spleen.  The  lymphatic  glands  in  many  instances  show  fibrosis,  and 
may  show  patches  where  there  is  an  invasion  of  the  "  Gaucher  cells." 
The  bone-marrow  may  show  similar  cells  either  in  groups  or  scattered 
irregularly.  These  organs  contain  granules  of  yellow  pigment,  some  of 
which  may  give  the  iron  reaction.  An  association  with  tuberculous 
lesions  has  been  noticed,  but  this  is  probably  accidental. 

Symptoms. — The  spleen  is  greatly  enlarged.  Later,  the  liver  en- 
larges and  may  reach  an  enormous  size.  Ascites  is  very  uncommon. 
The  superficial  lymph  nodes  are  not  enlarged.  Jaundice  has  been 
noticed,  but  appears  to  be  exceptional.  More  usually  the  skin  shows 
a  brown  or  a  peculiar  grey  discoloration.  A  brownish-yellow  wedge- 
shaped  thickening  of  the  conjunctiva  beginning  at  the  nasal  side  of  the 
cornea  is  described  by  Brill  and  Mandlebaum.  The  temporal  side 
shows  this  change  at  a  later  stage.  Emaciation  becomes  a  marked 
feature  as  the  disease  advances,  but  the  patient  retains  a  remarkable 
sense  of  comfort  and  well-being  for  a  surprisingly  long  period.  There 
is  usually  a  hemorrhagic  tendency.  There  may  be  spontaneous  haemor- 
rhages  from    such  situations  as  the   gums,  and  bleeding  after   tooth 


184  SPLENIC   ANEMIA— PHAGOCYTIC   ANAEMIA 

extraction  or  wounds  may  give  rise  to  trouble.  The  blood  changes  are 
often  not  characteristic,  but  some  degree  of  anaemia  always  develops 
sooner  or  later.  Ked  cells  may  be  diminished  to  three  millions, 
haemoglobin  is  more  reduced,  and  normoblasts  may  be  found.  The 
leucocytes  are  either  unaffected  or  there  may  be  a  slight  leucopenia. 

Diagnosis. — A  history  of  several  members  of  a  family  being 
affected,  the  presence  of  pigmentary  changes  other  than  jaundice,  the 
early  development  of  enormous  enlargement  of  the  spleen  and  liver, 
the  late  incidence  of  anaemia,  the  existence  of  leucopenia  and  a  tendency 
to  haemorrhage,  the  eye  symptoms  and  absence  of  ascites  and  of 
subjective  symptoms,  would  strongly  suggest  this  condition. 

Prognosis. — The  course  in  primary  splenomegaly  may  be  very 
prolonged.  In  Gaucher's  own  case  the  spleen  had  been  enlarged  for 
twenty-five  years.  The  patient  may  have  little  discomfort  for  a  very 
long  time. 

Treatment. — General  treatment  may  be  carried  out  on  the  same 
lines  as  in  Banti's  disease.  Brill  and  Mandlebaum  quote  eight  splenec- 
tomies in  fourteen  cases.  Three  died  as  the  result  of  operation,  and  in 
•one  case  the  liver  continued  to  enlarge.  They  doubt  whether  the 
progress  of  a  disease  affecting  the  whole  haeniopoietic  system  can  be 
benefited  by  the  removal  of  one  organ  only ;  but  as  more  benefit  has 
followed  from  splenectomy  than  from  any  other  measure  it  is  probably 
the  best  treatment  at  present  available. 

Literature 

Kisel,  Ziegler's  Beitrage,  xlvi.  2.  Brill,  Mandlebaum  and  Libman,  Amer. 
Journ.  of  the  Med.  Sciences,  June  1909.  Brill  and  Mandlebaum,  Amer.  Journ. 
of  the  Med.  Sciences,  December  1913. 

Phagocytic  Anaemia 

Van  ISTuys  and  Kowley  have  described  cases  in  which  there  was 
very  marked  anaemia,  apparently  due  to  a  very  great  phagocytosis  of 
red  cells  in  the  circulating  blood.  All  the  varieties  of  leucocytes, 
including  myelocytes  and  what  were  taken  to  be  plasma  cells,  took 
part  in  the  phagocytosis,  and  leucocytes  were  ingested  as  well  as  red 
corpuscles. 

In  Rowley's  case  the  type  of  anaemia  varied  curiously  from  day  to 
day.     At  one  time  there  were  small  corpuscles  and  normoblasts,  with 


SPLENIC   ANAEMIA— PHAGOCYTIC   ANEMIA  185 

low  colour  index,  at  others  there  were  megaloblasts,  large  red  cells, 
and  high  colour  index.  The  number  of  leucocytes  was  greatly  increased ; 
the  normal  proportions  were  not  much  disturbed,  but  myelocytes  and 
plasma  cells  were  present.  Injection  of  five  drops  of  the  patient's 
blood  into  a  guinea-pig  caused  in  two  weeks'  time  a  marked  phago- 
cytosis of  the  red  corpuscles.  The  phenomenon  lasted  for  nearly  two 
months.  The  condition  is  ascribed  to  the  presence  of  auto-opsonins  in 
the  blood. 

Hopkins  has  recorded  a  case  in  which  'phagocytosis  developed  in 
the  blood  of  a  case  of  pernicious  anaemia  after  transfusion. 

Literature 

Kowley,  Joum.  of  Exper.  Med.,  x.  1908.      Van  Nuys,  Boston  Med.  and 
Surg.  Joum.,  clvi.  1907.     Hopkins,  Archiv.  of  Int.  Med.,  vi.  1910. 


CHAPTEE  XIX 

HEMATOGENOUS   CYANOSIS— HEMOCHROMATOSIS— 

LIPEMIA 

HEMATOGENOUS   CYANOSIS 

Apaet  from  diseases  of  the  heart  and  lungs,  cyanosis  may  be  due  to 
changes  in  the  blood.  There  may  be  an  abnormally  high  blood-count 
with  enlargement  of  the  spleen  (splenomegalic  polycythemia).  On 
the  other  hand  the  blood-count  may  be  normal,  but  there  is  some 
alteration  in  the  blood-pigment.  The  most  common  abnormal  pigment 
is  methsemoglobin.     Sulphhseinoglobinsemia  also  occurs. 

Splenomegalic  Polycythemia — Erythremia 

This  condition,  first  described  by  Yaquez  in  1892,  is  characterised 
by  an  increase  in  the  number  of  red  blood  corpuscles  with  cyanosis 
and  enlargement  of  the  spleen. 

Etiology. — Most  of  the  recorded  cases  have  occurred  between  the 
ages  of  thirty-five  and  fifty,  but  the  disease  may  possibly  be  congenital 
in  some  instances.  Nothing  more  convincing  than  mental  worry  has 
been  suggested  as  an  exciting  cause. 

Morbid  Anatomy  and  Pathology. — Examination  of  the  shafts  of 
the  long  bones  shows  that  there  is  an  increased  activity  of  red  blood 
corpuscle  formation.  The  yellow  marrow  is  completely,  or  in  large 
part,  converted  into  red  marrow.  In  some  cases  the  erythroblastic 
function  does  not  appear  very  active,  but  the  great  increase  in  area 
accounts  for  a  large  output  of  red  corpuscles  into  the  circulation. 

There  is  also  an  increase  of  leucoblastic  activity,  a  condition  which 
is  always  associated  with  increased  erythropoiesis.  It  is  a  curious 
fact,  however,  that  the  leucocytes  in  such  a  marrow  do  not  neces- 
sarily appear  in  increased  numbers  in  the  peripheral  circulation 
(see  Pernicious  Anasmia). 

The  spleen  is  enlarged,  the  pulp  being  hyperplastic  and  engorged 


HEMATOGENOUS   CYANOSIS  187 

with  blood,  and  infarctions  are  commonly  noted.  The  liver  and  other 
organs,  as  well  as  the  splanchnic  vessels,  show  great  congestion.  In 
a  few  cases  there  have  been  arteriosclerosis  and  a  moderate  degree 
of  cardiac  hypertrophy.  The  blood-pressure  is  raised  in  typical  cases, 
sometimes  very  considerably.  This  feature  is  apparently  most  marked 
in  the  rare  cases  in  which  there  is  no  discoverable  splenic  enlargement. 
As  a  result  of  the  increased  output  of  red  (and  sometimes  white) 
corpuscles  there  is  dilatation  of  vessels  and  capillaries  and  increased 
viscosity  of  the  blood.  Possibly  symptoms  may  be  masked  for  some 
time  by  an  increased  arterial  blood-pressure,  but  by  the  time  cases 
come  under  observation  there  is  cyanosis,  and  sometimes  thrombosis, 
haemorrhage,  or  other  local  circulatory  disorders. 

Symptoms. — The  onset  is  gradual.  Lassitude  and  headache  are 
perhaps  the  earliest  symptoms.  Dyspepsia,  abdominal  pain  and 
tenderness  associated  with  the  enlarged  spleen,  thirst,  and  constipation 
are  commonly  present,  but  the  condition  is  compatible  in  some  cases 
with  great  physical  and  mental  activity,  and  the  absence  of  any  but 
occasional  symptoms.  The  liver  may  be  slightly  enlarged.  The 
spleen  always  shows  definite  increase  in  size.  The  degree  of  enlarge- 
ment may  vary  throughout  the  course  of  the  disease. 

Cyanosis  is  the  rule,  but  it  may  be  absent.  The  degree  of  blueness 
may  be  intensified  by  exposure  to  cold  or  by  emotional  conditions.  The 
mucous  membranes  show  the  condition  as  well  as  the  skin.  Haemor- 
rhages from  the  various  mucous  surfaces  have  been  recorded. 
Vascular  engorgement  may  be  seen  with  the  ophthalmoscope.  The 
blood-pressure  is  frequently  above  normal.  Slight  cutaneous  pig- 
mentation has  occurred  in  a  few  cases.  A  white  line  may  sometimes 
be  induced  by  cutaneous  irritation,  and  actual  dermatographia  has 
been  noticed. 

The  condition  of  the  urine  varies.  It  is  usually  abundant,  and 
may  be  clear,  but  often  contains  considerable  quantities  of  urobilin. 
Albuminuria  in  varying  degree  may  occur,  and  is  often  associated  with 
the  presence  of  tube-casts. 

Blood  Changes. — The  red  cells  are  increased  in  number,  counts 
varying  from  7  to  12  millions  per  c.mm.  There  is  no  great  diminu- 
tion in  their  size,  so  that  counts  much  larger  than  12  millions  could 
hardly  be  obtained,  although  Koester  has  found  13,600,000  per  c.mm. 
A  few  normoblasts  have  been  noted  in  some  of  the  cases.     The  hsemo- 


188  HEMATOGENOUS   CYANOSIS 

globin  value  may  reach  170  or  180  per  cent.,  but  the  colour  index  is 
usually  below  1.  The  white  cells  are  practically  always  increased  in 
number.  Counts  of  20,000  to  30,000  are  common.  The  increase  is 
accounted  for  by  the  polymorphonuclear  cells,  which  frequently  amount 
to  more  than  80  per  cent,  of  the  total.  Myelocytes  are  sometimes  seen. 
In  Blumenthal's  case  there  were  16,000  white  cells  per  c.mm.,  with 
36  per  cent,  myelocytes.  No  observations,  so  far  as  we  know,  have 
been  made  on  the  number  of  blood-plates.  The  specific  gravity  of  the 
blood  is  increased.  The  viscosity  is  increased  in  proportion  to  the 
polycythemia.  No  constant  change  in  relation  to  coagulability  has 
been  noted.  Cryoscopic  examination  has  given  negative  results 
(Senator,  Parkes  Weber).  The  total  volume  of  the  blood,  as  tested 
by  the  carbon  monoxide  method  of  Haldane  and  Lorrain  Smith,  is 
considerably  increased. 

Course. — Many  cases  show  little  change,  either  for  better  or  worse, 
for  prolonged  periods.  Complications,  apart  from  intercurrent  affections, 
are  not  common,  and  are  usually  vascular  disturbances.  Erythromelalgia 
appears  to  be  one  of  the  most  frequent.  Haemorrhages  from  mucous 
membranes  may  occur,  and  after  the  first  shock  is  over,  may  improve 
the  patient's  condition  by  reducing  the  blood-count  to  more  normal 
figures  and  lowering  the  blood-pressure. 

Eemissions  for  varying  periods  have  been  observed,  and  on  the  other 
hand  sudden  exacerbations  of  the  cyanosis  are  not  infrequent.  The  end 
is  usually  associated  with  one  of  these  exacerbations,  a  vascular  brain 
lesion,  or  an  intercurrent  affection. 

Treatment. — The  same  careful  regime  as  would  be  applicable  to 
any  vascular  disorder  is  indicated  in  this  condition.  Stimulants,  vaso- 
dilators, and  those  drugs  (phenacetin,  etc.)  which  have  been  known 
to  cause  polycytliEemia  are  all  to  be  avoided. 

Drugs  such  as  arsenic  and  iron,  which  are  capable  of  stimulating 
the  bone-marrow,  are  contra-indicated.  Perhaps  it  would  be  worth 
while  to  take  some  steps  to  diminish  the  amount  of  iron  in  the  food. 
A  diet  consisting  largely  of  milk  and  rice  preparations  might  therefore 
be  tried. 

Subjective  symptoms  have  been  benefited  both  by  spontaneous  and 
therapeutic  bleeding.  The  blood-pressure  would  perhaps  be  the  best 
guide  to  the  advisability  of  venesection  in  any  given  case.  A  large 
number  of   drugs  have  been    tried.      A   moderate  amount  of   success 


HEMATOGENOUS   CYANOSIS  189 

has  followed  inunction  of  biniodide  of  mercury  over  the  spleen,  the 
administration  of  quinine,  and  the  prolonged  administration  of  thyroid 
gland  or  iodothyrin. 

Eontgen  rays  applied  over  the  spleen  and  long  bones  have  given 
inconsistent  results.      No  benefit  is  to  be  expected  from  splenectomy. 

Literature 

Parkes  "Weber  {Quart.  Journ.  of  Med.,  ii.  1908)  and  Watson-Wemyss 
(Edin.  Med.  Jmirn.,  February  1911)  give  critical  reviews,  with  full  references 
to  date. 

Methemoglobinemia 

Etiology. — This  condition  is  caused  either  by  the  absorption  of 
nitrites  from  the  intestine  in  cases  of  diarrhoea,  or  by  drug  poisoning. 
The  most  common  drug  to  cause  cyanosis  is  acetanilide,  which  forms 
the  basis  of  most  "  headache  powders  "  in  the  market.  Phenacetin, 
sulphonal,  trional,  veronal,  potassium  chlorate,  and  the  nitrites  may 
produce  the  same  effect.  Workers  in  these  drugs  and  also  in  aniline 
dyes  are  not  uncommonly  affected. 

Symptoms. — In  acute  cases  there  may  be  severe  dyspnoea  with  a 
certain  degree  of  heart  failure;  in  more  chronic  cases  headache  and 
prostration  may  be  the  only  symptoms  beyond  the  cyanosis ;  in  the 
intestinal  (nitrite)  cases  there  is  diarrhoea.  Spectroscopic  examination 
of  the  blood  shows  a  dark  band  in  the  red  near  the  line  C,  which 
disappears,  to  be  replaced  by  the  band  of  reduced  haemoglobin,  on  the 
addition  of  a  few  drops  of  ammonium  sulphide  and  the  application 
of  gentle  heat. 

Treatment. — In  the  acute  cases  due  to  drugs,  emetics  or  lavage  of 
the  stomach  may  be  required.  The  patient  should  have  plenty  of  fresh 
air,  and  must  be  kept  warm.  Cardiac  stimulants  may  be  required. 
In  the  chronic  cases  the  drug  must  be  stopped ;  in  the  intestinal  cases 
the  methasmoglobinEemia  will  clear  up  within  forty-eight  hours  on  a 
purely  milk  diet,  but  the  symptoms  return  within  four  hours  after  a 
full  meal.  It  is  important  that  diarrhoea  should  not  be  treated  with 
subnitrate  of  bismuth,  since  certain  intestinal  bacteria  may  change 
nitrates  into  nitrites.  Fatal  cases  were  reported  when  this  drug  was 
in  use  in  connection  with  X-ray  diagnosis.  Idiosyncrasy  may,  of 
course,  play  a  part  in  them.  The  methsemoglobinuria  disappears  as  the 
enteritis  is  cured. 


190  HEMATOGENOUS   CYANOSIS 

Microbic  Cyanosis 

Under  this  name  Gibson  and  Douglas  *  recorded  the  case  of  a 
married  lady  suffering  from  headaches,  giddiness,  and  a  tendency  to 
faintness,  with  cyanosis.  Eed  cells,  3,360,000  ;  Hb  70  per  cent. ;  leuco- 
cytes, 10,296.  Methsemoglobin  was  found  in  the  blood.  Nitrites  were 
found  in  the  blood,  but  only  in  traces  in  the  faeces.  An  organism,  either 
B.  coli  or  a  closely  allied  bacillus,  was  grown  from  the  blood.  The 
suggestion  was  made  that  an  infection  of  the  blood  from  the  bowel  had 
occurred,  and  that  a  hsematogenous  formation  of  nitrites  was  keeping  a 
varying  amount  of  haemoglobin  in  a  condition  of  methsemoglobin,  thus 
leading  to  false  cyanosis.  Improvement  followed  a  course  of  intestinal 
antiseptics. 

SULPHH^MOGLOBINiEMIA 

Etiology  and  Pathology. — This  condition  results  from  the  hyper- 
formation  or  hyperabsorption  of  sulphuretted  hydrogen,  or  from  the 
presence  in  the  blood  of  an  abnormal  reducing  agent  acting  with  a 
small  trace  of  H2S.  Mackenzie  Wallis  2  has  studied  five  cases  and  found 
that  sulphhsemoglobin  partially  replaces  the  oxyhemoglobin  of  the 
blood  and  is  present  in  the  red  corpuscles  and  not  in  the  serum.  The 
serum  contained  a  strong  reducing  substance,  possibly  of  the  nature 
of  a  hydroxylamine,  capable  of  producing  reduction  of  the  oxyhemo- 
globin. This  is  an  essential  and  primary  stage  in  the  production  of 
sulphhsemoglobin. 

A  nitrite-producing  organism  was  found  in  the  saliva  of  all  the 
patients,  and  it  appeared  to  be  capable  of  evolving  the  reducing 
substance. 

Symptoms. — The  symptoms  are  similar  to  those  of  chronic  met- 
hsemoglobinsemia,  from  which  the  condition  is  distinguished  by  the 
spectroscope.  The  blood  shows  a  dark  band  in  the  red.  The  band 
persists  after  warming  the  blood  with  ammonium  sulphide,  and  may 
be  intensified  by  the  addition  of  a  reducing  agent  such  as  phenyl- 
hydrazine. 

The  blood  does  not  show  the  temporary  improvement  which 
occurs  in  metliEemoglobinsemia  when  a  milk  diet  is  taken.  West  and 
Clarke 3  have  described  a  case  with  5,050,000  red  cells  per  c.mm.,  Hb 

i  Lancet,  14th  July  1906. 

2  Quart.  Journ.  of  Med.,  vii.  1913,  p.  73. 

3  Lancet,  2nd  February  1907.     See  also  Clarke,  Med.  Record,  24th  July  1909. 


HEMATOGENOUS   CYANOSIS  191 

115  per  cent.  The  blood  gave  spectra  of  oxy haemoglobin  and  sulph- 
hEemoglobin.  H2S  was  not  found  free  in  the  patient's  blood,  but  it 
was  determined  experimentally  that  the  amount  of  H2S  required  to 
cause  an  appreciable  change  in  the  blood-pigment  at  body  temperature 
was  far  below  that  which  could  be  detected  by  chemical  means. 

Treatment. — Treatment  is  unsatisfactory.  If  constipation  or  gastro- 
intestinal symptoms  are  present  they  should  be  dealt  with,  but  it  is 
open  to  question  whether  the  intestine  plays  any  direct  part  in  the 
production  of  the  condition.  Wallis  successfully  treated  one  of  his 
cases  with  an  autogenous  vaccine  made  from  the  nitroso-bacillus  in  the 
saliva.     Similar  treatment  in  another  case  failed. 

HEMOCHROMATOSIS 

This  rare  condition  is  associated  with  bronzing  of  the  skin,  due  to  a 
deposition  of  hsemofuscin.  Part  of  the  pigment  contains  iron,  but  in 
a  more  firmly  combined  condition  than  in  hemosiderin.  There  is 
degeneration  of  the  cells  of  the  liver,  pancreas,  and  other  organs,  and 
cirrhotic  changes  due  either  to  the  pigment  or  to  a  hypothetical  toxin 
causing  the  condition.  The  late  stages  of  the  disease  may  be  associated 
with  diabetes  (diabdte  bronzd  of  French  writers). 

Literature 

Beattie,  Journ.  of  Path,  and  Bad.,  1903.  Roberts,  Brit.  Med.  Journ.,  11th 
November  1911.    Potter  and  Milne,  Amer.  Journ.  of  Med.  Science,  1912,  p.  46. 

Lipemia 

This  is  a  rare  condition  occurring  in  the  course  of  diabetes  mellitus. 
It  usually  affects  young  adults.  The  source  of  the  fat  in  the  blood  is 
most  probably  the  glucose.  The  condition  is  associated  with  acidosis. 
The  symptoms  of  diabetes  do  not  appear  to  be  much  modified  by  the 
presence  of  the  lipfemia.  The  melting-point  of  the  fat  is  below  the  body 
temperature,  and  when  cooled  the  fatty  particles  are  very  small.  The 
condition  is  diagnosed  by  the  examination  of  blood-films.  The  red 
corpuscles  do  not  readily  form  rouleaux,  and  they  are  somewhat  cloudy 
in  appearance.  In  one  of  Fraser's  cases  there  was  a  leucocytosis  of  23,000. 
In  the  plasma  are  numerous  particles,  highly  refractiie  and  showing 
Brownian  movement.  They  may  be  found  also  in  some  of  the  large 
lymphocytes.     These  particles  can,  as  a  rule,  be  stained  with  osmic  acid 


192  HEMATOGENOUS   CYANOSIS 

or  sudan.  Hale  White,  however,  reports  a  case  of  diabetes  in  which 
there  was  a  granular  precipitate  in  the  blood  plasma.  This  did  not  give 
the  ordinary  reactions  of  fat,  but  appeared  to  be  a  protein  precipitated 
by  the  presence  of  a  fatty  substance,  probably  an  ester  of  cholesterin 
with  one  or  more  of  the  higher  fatty  acids. 

Cases  can  also  be  distinguished  by  the  remarkably  white  appearance 
presented  by  the  retinal  vessels.  In  one  of  Fraser's  cases  the  percentage 
of  fat  in  the  blood  amounted  to  12,  in  another  to  16. 

Treatment. — Fraser  states  that  he  has  seen  the  disappearance  of 
fatty  droplets  from  the  blood  in  one  case  of  diabetes  under  the  influence 
of  alkaline  treatment.  He  recommends  the  frequent  examination  of 
the  urine  of  diabetics  for  the  presence  of  /3-oxy butyric  acid,  and  of  the 
blood  for  fat,  especially  in  the  case  of  young  subjects.  The  finding  of 
either  is  an  indication  for  treatment  by  a  liberal  administration  of 
alkalies. 

Literature 

Fischer,  Virchoufs  Archiv,  Bd.  clxxii.  Fraser,  Scottish  Med.  Journ.,  Septem- 
ber 1903.  Hale  White,  Lancet,  10th  October  1903.  Turney  and  Dudgeon, 
Journ.  of  Path,  and  Bad.,  xi.  1906. 


CHAPTER  XX 

LEUCOCYTHiEMIA— LEUKAEMIA 

Definition. — A  disease  characterised  by  a  persistent  increase  of  white 
cells  in  the  blood. 

Classification.  —  The  disease  occurs  in  different  forms.  When 
Ehrlich  first  introduced  methods  of  differential  staining  of  leucocyte 
granules  he  made  a  sharp  distinction  between  the  lymphocytes  or  non- 
granular cells,  on  the  one  hand,  and  the  neutrophil,  eosinophil,  and 
basophil  leucocytes  on  the  other.  He  regarded  all  the  lymphocytes  as 
being  derived  from  the  lymphatic  glands  and  lymphoid  tissues  and  the 
granular  cells  as  taking  origin  in  the  bone-marrow. 

He  therefore  divided  leucocythaemia  into  lymphatic  and  medullary, 
considering  the  first  was  a  disease  of  the  lymphatic  glands  and  the 
latter  a  disease  affecting  the  bone  marrow.  Subsequent  research  has 
altered  this  conception  in  several  directions. 

It  is  now  known  that  all  the  leucocytes  are  derived  from  a  common 
ancestor,  the  primitive  leucocyte,  which  so  closely  resembles  the  large 
lymphocyte  of  the  blood  as  to  be  indistinguishable  from  it.  It  has 
been  pointed  out  by  Pappenheim,  Walz,  and  ourselves  that  cases  of 
lymphatic  leukaemia  may  occur  without  any  glandular  enlargement. 
In  these  cases  the  marrow  showed  marked  lymphoid  hyperplasia.  It 
therefore  became  necessary  to  revise  our  views,  and  it  was  recognised 
that  while  there  was  a  distinction  between  lymphatic  leuksemia  and 
myelocythsemia,  the  former,  as  well  as  the  latter,  might  be  a  disease  of 
the  bone-marrow. 

But  a  new  difficulty  has  arisen.  Naegeli  has  made  a  division  of  the 
large  lymphocytes  into  large  lymphocytes  proper  and  myeloblasts  (p.  68). 
The  latter  acquire  granules  and  become  pro-myelocy tes,  then  myelocytes, 
then  polymorphs. 

These  myeloblasts  can  only  be  distinguished  by  special  modern 
methods  of  staining,  but  the  distinction  finds  confirmation  in  the 
oxydase  reaction.  Myeloblasts  give  a  positive  reaction,  lymphocytes 
do  not.     But  here  matters  are  complicated  by  Dunn's  observation  that 

193  13 


194  LEUCOCYTILEMIA— LEUKEMIA 

myeloblasts,  early  enough  in  their  life  history,  fail  to  give  a  positive 
oxydase  reaction.  This  suggests  the  obvious  inference  that  lymphocytes 
may  acquire  the  oxydase  ferment  and  become  myeloblasts ;  in  other 
words,  that  the  myeloblasts  of  the  bone-marrow  have  arisen  from 
lymphocytes.  Time  and  subsequent  research  will  doubtless  arrange 
these  findings  in  true  perspective,  and  we  disclaim  any  desire  to 
minimise  their  interest  or  importance  from  the  cytological  stand- 
point. We  wish,  however,  to  point  out  that  too  great  insistence  on 
the  hematological  minutiae  may  bring  nothing  but  confusion  to  the 
mind  of  the  clinician.  Many  cases  of  leukaemia  in  which  the  pre- 
ponderating cells  have  been  thought  to  be  myeloblasts  have  been 
reported  as  instances  of  myeloid  leukaemia. 

Now  the  great  majority  of  leukaemias  with  non-granular  cells  run 
an  acute  course  and  have  the  same  general  symptoms,  whether  the 
preponderating  cells  are  myeloblasts  or  lymphocytes. 

A  week's  observation  will  readily  determine  whether  an  individual 
case  is  to  fall  into  the  comparatively  rare  chronic  type  of  non-granular 
leukaemia. 

The  great  majority  of  cases  of  leukaemia  with  a  preponderance  of 
granular  cells  run  a  chronic  course  with  different  symptoms,  and 
examples  of  granular-cell  leucocythaemia  which  run  an  acute  course 
are  excessively  rare. 

We  would  therefore  plead,  if  on  no  other  ground  than  as  a  concession 
to  the  clinician  who  may  have  little  knowledge  of  cytology,  that  the 
original  classification  of  Ehrlich  be  maintained  and  that  the  term 
myeloid  or  medullary  leukaemia  be  meantime  restricted  to  these  cases 
in  which  the  preponderating  cells  are  definitely  granular — myelocytes 
and  polymorphs — and  that  the  cases  in  which  the  preponderating  cells 
a,re  non-granular  be  termed  lymphatic  whether  the  cells  are  lymphocytes 
or  myeloblasts  in  the  histological  sense.  The  "  mixed  "  cases  might  be 
recorded  as  such. 

In  our  description  we  propose  to  follow  this  plan  and  the  following 
classification  will  be  adopted : — 

1.  Lymphatic  (non-granular)  leukaemia  (lymphocy thaemia ;  lymph- 
semia) — (a)  acute,  (b)  chronic.  2.  Myelogenous  (granular)  leukaemia 
(myelocythaemia ;  spleno-medullary  leucocythaemia;  myelaemia)  —  (a) 
chronic,  (b)  acute.  3.  Mixed  forms.  4.  Chloroma.  The  order  of 
frequency  of  these  forms  is,  in  our  experience,  acute  lymphocy  thaemia, 
chronic  myelocythaemia,  chronic  lymphocy  thaemia,  and  acute  myelo- 
cythaemia.    Mixed  forms  and  chloroma  are  about  equally  rare. 


LEUCOCYTH^EMIA— LEUKEMIA  195 

1.  Lymphatic  Leucocytelemia 

Etiology. — The  disease  is  by  far  most  common  in  children,  adoles- 
cents, and  young  adults.  It  may,  however,  occur  at  any  age.  We  have 
seen  an  acute  case  in  a  man  aged  sixty-one,  another  in  a  man  of  seventy- 
two,  and  Bramwell  records  a  case  of  chronic  type  beginning  at  the  age 
of  seventy-eight.  The  disease  is  much  more  frequent  in  males  than 
females. 

A  host  of  possible  causal  factors  has  been  suggested,  but  none  of 
them  have  been  sufficiently  common  to  amount  to  more  than  coinci- 
dence. Haemorrhage  has  frequently  been  alleged  to  be  a  cause  of  the 
disease,  but  it  is  much  more  likely  to  have  been  an  early  symptom. 

Morbid  Anatomy  and  Histology. — The  essential  feature  of  the 
disease  is  an  overproduction  of  lymphocytes  which  pass  into  the  blood- 
stream, infiltrate  the  various  tissues  and  organs,  except  the  central 
nervous  system,  and  lead  to  interference  with  nutrition.  Haemorrhages 
are  very  common. 

Alimentary  Canal. — There  is  sometimes  enlargement  of  the  tonsils. 
There  is  an  increase  of  lymphocytes  in  the  walls  of  the  stomach  and 
intestine,  and  in  some  cases  their  amount  is  so  great  as  to  cause  separa- 
tion of  the  tubules. 

Heart. — There  is  gross  lymphocytic  infiltration  of  the  heart  in  about 
half  of  the  cases.  An  extraordinary  degree  of  separation  of  the 
muscular  fibres  sometimes  occurs.  There  is  often  fatty  degeneration 
of  the  heart  muscle. 

Liver. — The  liver  may  be  slightly  enlarged.  It  is  often  the  seat  of 
very  great  infiltration.  There  may  be  masses  of  lymphocytes  visible  to 
the  naked  eye  under  the  capsule  and  in  the  portal  tracts.  The  lympho- 
cyte infiltration  begins  in  the  portal  tracts  and  at  the  periphery  of  the 
lobules,  but  may  extend  up  the  rows  of  liver  cells,  in  some  cases  right 
up  to  the  intralobular  vein.  In  extreme  cases  the  liver  may  be  repre- 
sented by  small  islands  of  hepatic  cells  lying  between  masses  of  invad- 
ing lymphocytes.  Cells  other  than  lymphocytes  are  uncommon  in  those 
areas,  but  sometimes  cells  resembling  the  giant  cells  of  bone-marrow 
may  be  found,  and  large  phagocytic  cells  ingesting  lymphocytes  and 
red  cells  are  sometimes  present. 

The  liver  cells  may  look  healthy  but  are  often  fatty.  They  always 
contain  a  large  amount  of  granular  pigment,  which  gives  the  reaction 
for  free  iron  in  the  majority  of  cases.     The  pigment  is  chiefly  found  at 


196  LEUCOCYTILEMIA— LEUKAEMIA 

the  periphery  of  the  lobules,  and  in  the  acute  cases  is  sometimes  as 
abundant  as  in  pernicious  anaemia  or  any  other  condition. 

Kidneys. — The  kidneys  are  usually  enlarged  and  show  massive  in- 
filtration leading  to  alteration  of  structure.  There  are  often  haemor- 
rhages which  may  give  rise  to  a  remarkable  "  piebald "  appearance. 
The  haemorrhages  often  destroy  areas  of  cortical  substance.  Massive 
lymphocyte  infiltration  is  the  rule ;  it  may  lead  in  some  cases  to  atrophy 
and  fibrosis  of  some  of  the  glomeruli.  Large  phagocytes  are  sometimes 
to  be  seen  ingesting  lymphocytes  in  the  infiltrated  areas. 

Spleen. — The  spleen  is  always  enlarged,  but  in  the  very  acute  cases 
the  enlargement  may  be  very  slight.  The  Malpighian  bodies  are  gener- 
ally atrophied,  rarely  normal.  We  have  never  seen  them  enlarged. 
The  pulp  is  generally  packed  with  lymphocytes,  and  among  them  there 
are  large  phagocytic  cells  ingesting  them.  The  endothelial  cells  of  the 
sinuses  are  exceedingly  prominent  and  may  be  cubical  or  columnar  in 
shape.  There  is  a  considerable  number  of  giant  cells  of  bone-marrow 
type.  There  is  nearly  always  a  fair  amount  of  pigment,  which  often 
gives  the  iron  reaction.  In  a  few  cases  there  is  a  considerable  fibrosis 
of  the  pulp. 

Lymphatic  Glands. — In  the  great  majority  of  cases  the  lymphatic 
glands  are  enlarged,  but  this  is  not  an  absolute  rule.  We  commonly 
find  that  the  more  chronic  the  course  of  the  disease  the  greater  size  do 
the  glands  attain  and  the  more  numerous  are  the  glands  affected.  In 
chronic  cases  nearly  every  gland  in  the  body  may  be  enlarged,  and  many 
of  them  may  be  as  big  as  a  large  walnut. 

The  enlarged  glands  show  packing  with  lymphocytes  to  such  an 
extent  that  all  distinction  between  cortex  and  medulla  is  lost,  and 
sections  show  a  remarkable  uniformity  of  structure.  The  blood-vessels 
are  large  and  no  longer  show  the  typical  arrangement.  Germ  centres 
are  not  found.  There  are  often  phagocytes  and  sometimes  giant  cells 
in  the  pulp.  The  lymphocytes  sometimes  show  a  remarkable  condition 
of  branching  or  karyorrhexis  of  the  nucleus. 

Haemolymph  glands  are  generally  unrecognisable  as  such  owing  to 
the  packing  of  the  sinuses  with  lymphocytes.  Normoblasts  are  some- 
times to  be  seen  in  the  sinuses,  and  phagocytosis  of  lymphocytes  and 
red  cells,  with  the  subsequent  pigmentary  changes,  is  not  uncommon. 
The  thymus  is  not  enlarged  and  usually  shows  little  change. 

Bone-Marrow. — The  yellow  marrow  is  always  replaced  to  a  large 
extent  or  entirely  by  red  marrow.  The  fat  has  in  many  cases  com- 
pletely disappeared,  and  sections  show  an  even  distribution  of  lympho- 


Plate  IX 


Fig.  1. — Section  of  Bone-Marrow  from  Case  of  Acute  Lymphatic 
Leuk/Emia  (Eosine  and  Methylene  Blue). 

Shows  great  proliferation  of  lymphocytes,  mostly  small.  Some  show 
curious  branching  or  karyorrheetic  nuclei,  others  show  mitosis. 

There  are  two  normoblasts  and  two  megaloblasts  and  very  few  granular 
leucocytes. 

A  phagocytic  giant  cell  contains  seven  erythrocytes  and  two  lympho- 
cytes. 


Fio.  2.—  Section  of  Bone-Marrow  from  Case  of  Myelocyth^emia. 

Shows  numerous  neutrophil  and  eosinophil  myelocytes  and  a  large 
number  of  lymphocytes.     Normoblasts  are  fairly  numerous. 


A.  G.,  fecit. 


LEUCOCYTELEMIA— LEUKAEMIA  197 

cytes  with  a  fair  number  of  red  corpuscles.  The  lymphocytes  are  both 
large  and  small,  but  in  most  cases  one  or  other  variety  seems  to  pre- 
ponderate in  overwhelming  numbers. 

Erythrocytes  are  generally  the  next  most  numerous  type  of  cell 
and  then  myelocytes,  but  their  proportions  to  the  lymphocytes  are  very 
small.  Normoblasts  are  present  in  small  numbers  and  megaloblasts 
are  sometimes  seen.  Giant  cells  are  scanty  and  degenerated.  Iron- 
containing  pigment  is  often  present.     Phagocytosis  is  usually  seen. 

Relation  of  the  Morbid  Changes  to  Pathology. — The  occasional 
absence  of  infiltration  from  the  alimentary  tract  and  its  moderate  amount 
when  present  appears  to  exclude  the  alimentary  canal  from  any  causal 
connection  with  the  disease,  and  we  do  not  find  any  special  tendency 
to  alimentary  disorder  in  the  previous  history. 

The  degenerative  changes  found  in  the  liver  are  not  peculiar  to  this 
disease.  The  large  amount  of  iron  pigment  often  found  is  accounted  for 
by  storage  of  iron  derived  (1)  from  normal  corpuscles  and  not  again 
utilised  by  an  inefficient  marrow ;  (2)  from  haemorrhages ;  and  (3)  from 
specially  vulnerable  corpuscles  developed  late  in  the  disease.  The 
evidence  afforded  by  the  changes  in  the  spleen  suggests  that  the 
accumulation  of  lymphocytes  in  the  pulp  is  due  to  a  passive  accumula- 
tion there  rather  than  an  increased  production.  On  the  other  hand, 
there  is  strong  evidence  of  destruction  of  lymphocytes  by  the  phago- 
cytic action  of  large  cells  in  the  pulp  and  by  endothelial  cells  pro- 
liferated from  the  walls  of  the  sinuses.  So  many  cases  have  now  been 
published  and  seen  by  ourselves  in  which  the  lymphatic  glands  were 
not  affected  that  we  believe  that  they  have  no  primary  causal  relation 
to  the  disease. 

The  bone-marrow  in  all  cases  shows  proliferation  of  lymphocytes 
to  such  an  extent  as  almost  entirely  to  replace  the  other  varieties  of 
cells.  This  change  may  exist  without  glandular  enlargement,  conse- 
quently we  regard  the  bone-marrow  as  the  primary  and  essential  seat 
of  the  disease. 

It  may  be  noted  that  patients  do  not  die  of  the  increase  of 
leucocytes,  but  rather  of  the  anaemia  which  coexists  or  of  inter- 
current diseases  (except  in  so  far  as  haemorrhages  may  be  due  to 
thrombosis  of  vessels  by  masses  of  leucocytes).  The  anaemia  is  more 
marked  in  proportion  as  the  condition  is  more  acute,  because  the  avail- 
able space  for  erythrocyte  production  is  rapidly  taken  up  by  lympho- 
cytes, and  the  spread  in  the  fatty  marrow  is  a  spread  of  lymphocytes 


198  LEUCOCYTH^EMIA— LEUKEMIA 

and  not  of  erythroblasts.  As  a  result  of  this,  when  the  normal  red 
corpuscles  in  the  blood  die  out  in  the  ordinary  course  their  place  will 
not  be  taken  by  new  ones  of  normal  type,  but  by  the  badly  formed  red 
corpuscles  which  always  appear  when  there  is  an  extra  demand  for 
these  corpuscles  and  an  insufficient  supply,  and  ultimately  by  normo- 
blasts and  even  megaloblasts.  A  further  cause  of  anaemia  is  the 
ingestion  of  red  cells  by  the  phagocytes  which  are  so  numerous  in 
this  condition  and  by  endothelial  cells.  The  iron  derived  from  the 
haemoglobin  of  the  destroyed  corpuscles  is  either  retained  in  the 
phagocytes  and  endothelial  cells  in  the  various  organs  in  which  the 
process  of  phagocytosis  goes  on,  or,  in  the  case  of  red  cells  which 
are  destroyed  in  the  blood-stream  itself,  is  taken  up  by  the  liver  cells 
and  retained  there,  partly  because  the  functions  of  the  liver  itself  are 
interfered  with  by  the  disease,  partly  because  there  is  little  or  no 
demand  for  it  for  the  production  of  new  red  cells.  In  the  chronic  cases 
the  anaemia  is  never  so  severe  as  in  the  acute  cases,  apparently  because 
the  change  in  the  marrow  is  slower,  so  that  erythroblastic  proliferation 
can  proceed  pari  passu  with  lymphocyte  proliferation ;  and  in  the 
extremely  chronic  cases  it  seems  probable  that  supplemental  erythro- 
cyte formation  takes  place  in  the  liver  and  spleen,  as  indicated  by  the 
presence  of  normoblasts  and  giant  cells.  A  long  time,  however,  must 
elapse  before  this  is  brought  about. 

It  seems  to  us  that  these  considerations  are  sufficient  to  account  for 
the  anaemia  without  the  operation  of  a  hypothetical  toxic  condition. 

The  same  applies  to  the  polymorphs.  The  frequency  with  which 
cases  of  lymphatic  leukaemia  die  of  pneumonia  and  other  intercurrent 
diseases  may  be  explained  by  the  fact  that  the  granular  cells  which 
respond  defensively  to  infection  by  the  pneumococcus,  for  instance, 
are  very  few  in  number  in  the  marrow,  having  been  crowded  out  by 
lymphocytes,  and  that  the  patient's  resistance  is  hampered  by  the 
small  number  of  polymorphs  which  he  can  muster  against  the  infection. 
As  bearing  this  out,  it  may  be  quoted  that  we  have  found  some  evidence 
of  supplemental  granulocyte  formation  in  the  spleen  and  other  organs — 
myelocytes  and  eosinophil  myelocytes  were  found  more  frequently  than 
normal. 

While  patients  do  not  die  directly  of  the  leucocyte  increase,  there 
can  be  no  doubt  that  the  enormous  deposits  and  infiltrations  in  organs 
must  interfere  greatly  with  their  functions.  This  is  more  prominent 
in  some  organs  than  in  others.  For  example,  the  alimentary  tube  in 
our  cases  seems  to  have  suffered  comparatively  little  in  this  way,  the 


LEUCOCYTH^EMIA— LEUKEMIA  199 

heart  also  slightly,  while  tonsils,  lungs,  pancreas,  thyroid,  suprarenal, 
general  muscular  system,  etc.,  were  little  affected.  On  the  other  hand, 
apart  from  the  profound  alteration  in  the  true  hemopoietic  organs,  the 
kidney  is  almost  always  affected,  though  to  a  very  variable  extent,  and 
though  the  secreting  tubules  do  not  suffer  to  anything  like  the  extent 
that  they  do  in  pernicious  amemia.  The  liver  is  the  organ  which  is  most 
profoundly  affected,  and  all  its  functions  must  be  greatly  interfered 
with  by  the  pressure  on  its  secreting  cells  which  the  infiltration  causes. 

Pathology. — Much  interesting  speculation  has  centred  round  the 
question  of  the  cause  of  the  leukemic  change  in  the  bone-marrow.  The 
chief  points  may  be  briefly  recapitulated.  The  possibilities  are  that  the 
proliferation  may  be  due  to  some  chemiotactic  influence,  that  it  may  be 
of  the  nature  of  tumour  growth,  or  that  it  may  be  due  to  some  disturb- 
ance of  the  balance  of  nutrition  which  either  encourages  the  overgrowth 
of  lymphocytes  or  removes  some  restraint  on  their  development.  In  the 
present  state  of  our  knowledge  the  two  latter  possibilities  may  be  taken 
as  one,  and  the  question  may  be  asked  whether  the  condition  is  simply 
a  useless  overgrowth  of  lymphocytes,  for  useless  overgrowth  is  practi- 
cally synonymous  with  tumour  in  the  broad  sense  in  its  results,  though 
the  process  may  be  different  in  origin. 

As  regards  chemiotaxis,  it  may  be  taken  that  they  are  lymphocytes 
in  the  normal  bone-marrow,  and  that  certain  toxins  (whooping-cough, 
smallpox)  may  cause  a  chemiotactic  increase  of  lymphocytes  in  the 
blood. 

On  the  other  hand,  the  following  reasons  against  the  chemiotactic 
theory  may  be  adduced  : — 

1.  No  organismal  or  other  toxin  has  been  found  constantly  asso- 
ciated with  the  disease. 

2.  The  ordinary  channels  of  entry  of  infective  disease — the  ali- 
mentary canal  and  the  lungs — show  only  a  slight  degree  of  lymphocyte 
infiltration. 

3.  The  function  of  all  the  organs  in  which  infiltration  takes  place 
is  greatly  interfered  with.  The  chemiotaxis  known  to  be  associated, 
with  other  forms  of  disease  never  reaches  this  extraordinary  degree. 

4.  Lymphocyte  infiltration  occurs  in  organs  and  tissues  in  which 
it  seems  impossible  that  it  could  appear  in  response  to  any  known 
chemiotactic  stimulus.  We  may  instance  the  fatty  tissue,  the  heart 
muscle,  the  pancreas,  the  thyroid,  etc. 

5.  The  more  chronic  the  process  the  greater  the  infiltration  and  the 


200  LEUCOCYTELEMIA— LEUKiEMIA 

number  of  lymphocytes  in  the  blood  tend  to  be.  This  is  just  the  reverse 
of  the  usual  rule  in  the  case  of  response  to  known  chemiotactic  stimuli. 
Moreover,  the  actual  number  of  lymphocytes  in  the  blood  in  some 
lymphatic  leukaemias  is  much  greater  than  ever  occurs  in  infections. 

6.  It  is  difficult  to  believe  that  the  large  labile  lymphocytes  which 
are  found  in  many  cases  of  leukaemia  could  be  of  any  service  in  a 
chemiotactic  sense.  Infections,  however  severe  or  prolonged,  are 
associated  with  a  fairly  normal  type  of  cell  which  never  shows  the 
extravagance  in  size  or  the  extent  of  degeneration  which  is  common 
in  lymphatic  leukaemia. 

7.  In  chronic  lymphatic  leukaemia  symptoms  are  sometimes 
ameliorated  by  treatment  with  X-rays,  although  a  large  number  of 
lymphocytes  are  destroyed.  If  they  were  there  for  any  useful  purpose 
their  destruction  should  not  lead  to  improvement. 

8.  It  is  difficult  to  conceive  of  any  organised  chemiotactic  influence 
lasting  for  years  as  in  the  chronic  cases  and  keeping  up  and  increasing 
the  alterations  in  the  blood  and  throughout  the  body. 

The  following  points  seem  to  us  to  be  strongly  in  favour  of  the  view 
that  we  have  to  deal  with  a  useless  proliferation  of  lymphocytes : — 

(a)  It  is  is  impossible  to  distinguish  histologically  and,  except  for 
the  presence  of  the  green  tumours,  even  clinically  between  lymphatic 
leukaemia  and  chloroma.  In  the  latter  disease  there  is  a  formation 
of  true  multiple  tumours  which  may  erode  bone  and  other  tissues. 
Further,  it  must  not  be  forgotten  that  in  lymphatic  and  myeloid 
leukaemia  there  may  be  swellings  on  the  gums,  the  skin,  and  even 
the  alimentary  canal,  which  may  be  considered  analogous  to  the  tumours 
of  chloroma. 

(b)  The  nuclei  of  many  of  the  lymphocytes  in  a  fluid  mount  contain- 
ing a  nuclear  stain  are  stained  at  once,  while  the  polymorphs  remain 
colourless.  Normal  lymphocytes  do  not  show  the  same  early  staining. 
The  early  colouring  is  evidence  of  the  effete  character  of  the  cells.  The 
great  amount  of  phagocytosis  of  lymphocytes  in  the  organs  and  tissues 
points  in  the  same  direction. 

(c)  Lymphatic  leukaemia  is  invariably  fatal,  whether  in  the  acute  or 
chronic  form.     This  cannot  be  said  of  any  infection. 

The  only  real  difficulty  in  the  way  of  the  view  that  lymphaemia 
is  analogous  to  tumour  growth  is  the  widespread  growth  of  lympho- 
cytic marrow  in  so  many,  if  not  all,  of  the  bones.  It  is  a  little  difficult 
to  conceive  of  such  a  widespread  change  beginning  in  a  single  cell  or 
group  of  cells  as  a  tumour  does.      It  seems  more  probable  that  the 


LEUCOCYTHvEMIA— LEUKAEMIA  201 

disease  is  caused  primarily  by  some  disturbance  in  metabolism,  of  such 
a  kind  that  the  growth  of  lymphocytes  is  either  encouraged  or  perhaps, 
more  probably,  is  not  restrained  as  it  is  in  the  normal  organism. 

While  we  conclude  that  the  bone-marrow  is  the  primary  and  essential 
starting-point  of  the  disease,  we  have  still  to  consider  whether  the 
infiltration  of  organs  and  tissues  is  entirely  clue  to  packing  with 
lymphocytes  derived  from  the  marrow  and  deposited  by  the  blood. 
The  outstanding  fact  regarding  this  infiltration  is  its  irregular  and  ex- 
ceedingly capricious  incidence  both  as  regards  locality  and  amount.  In 
the  lymph  glands,  germ  centres,  the  normal  breeding-places  of  lympho- 
cytes, are  inconspicuous  or  absent.  In  the  spleen  the  Malpighian 
corpuscles  are  small  and  sometimes  fibrous,  and  the  Peyer's  patches 
and  other  masses  of  lymphoid  tissue  throughout  the  body  are  inactive. 
"We  do  not  consider  that  there  is  a  general  hyperplasia  throughout  the 
body  in  addition  to  the  bone-marrow  lesion.  The  lymphoid  tissues  are 
invaded,  and  the  invading  lymphocytes  may  and  do  undergo  mitosis 
and  give  rise  to  a  (metaplastic)  increase.  This  is  at  the  expense  of 
the  local  lymphoid  tissue,  as  is  evidenced  by  its  atrophy. 

Pappenheim  and  Hirschfeld1  have  recorded  a  case  of  acute 
lymphatic  leukaemia  in  which  there  was  the  usual  appearance  of 
the  marrow,  but  the  lymphatic  glands  showed  hyperplasia  of  the 
follicles.  The  Malpighian  bodies  in  the  spleen  were  greatly  hyper- 
trophied  and  to  some  extent  confluent.  The  liver  showed  circumscribed 
islands  of  small  lymphocytes  in  the  fibrous  tissue  rather  than  the  usual 
diffuse  change.  They  seek  to  separate  lymphatic  leuksemia  into  two 
types — myeloplastic  and  lymphoplastic.  In  the  course  of  a  large 
experience  of  the  disease  we  have  never  seen  a  case  of  the  lymph- 
adenoid  or  lymphoplastic  type.  Granting  its  existence  as  a  change 
secondary  to  the  bone-marrow  disease,  it  does  not  much  alter  the 
conception  of  the  disease  we  have  set  out.  In  our  opinion  all  the 
cases  which  show  the  typical  blood  changes  of  lymphatic  leuksemia 
have  their  origin  in  the  bone-marrow,  but  it  must  be  admitted  that  the 
view  that  the  disease  is  the  expression  of  a  general  lymphatic  hyper- 
plasia is  widely  held.  There  is  no  essential  distinction  as  regards  their 
pathology  between  the  acute  and  chronic  cases. 

Symptoms. — (a)  Acute  Zymjrfiatic  Leukcemia. — The  onset  may  be 
insidious,  but  more  commonly  the  initial  symptoms  are  severe.  A 
slight  enlargement  of  a  small  group  of  glands  may  be  noticed,  usually 

1  Folia  Hcematologica,  v.  1908. 


202  LEUCOCYTH^MIA— LEUKEMIA 

about  the  neck.  This  may  remain  unaltered,  or  the  swelling  may 
rapidly  increase  and  be  followed  by  enlargement  of  other  groups. 
Extravasations  of  blood  into  the  skin  may  call  attention  to  the  con- 
dition. Haemorrhage  from  mucous  membranes  is  a  common  initial 
symptom,  especially  from  the  nose  and  the  gums.  Some  cases  begin 
as  an  acute  febrile  attack  without  very  definite  symptoms  and  without 
enlargement  of  glands.  There  may  be  pain  in  the  long  bones  or  over 
the  sternum.  There  may  be  little  change  in  the  clinical  picture  from 
first  to  last.  There  is,  of  course,  increasing  weakness,  and  there  is 
always  progressive  anaemia,  with  breathlessness,  faintness,  and  dyspnoea. 
When  the  disease  is  fully  established  in  a  typical  case  the  tempera- 
ture is  about  102°  F. ;  the  face  has  a  pale  waxy  appearance.  The 
mucous  membranes  are  exceedingly  pale.  There  may  be  no  enlargement 
of  glands,  but  occasionally  there  may  be  groups  of  enlarged  glands  in 
the  submaxillary  region,  neck,  axillae,  groins,  and  popliteal  spaces, 
while  even  the  epitrochlear  and  others  not  so  commonly  noticed  may 
be  involved.  These  widespread  enlargements  are  more  common  in  the 
less  acute  cases.  The  tonsils  may  be  enlarged.  The  abdomen  may  be 
prominent  from  enlargement  of  mesenteric  and  retroperitoneal  glands. 
The  spleen  is  always  enlarged,  but  the  extent  of  the  enlargement  varies 
very  greatly.  As  a  rule,  the  more  acute  the  case  the  less  enlargement  will 
there  be.  The  liver  also  may  show  a  moderate  increase  in  size.  There 
may  be  nausea  and  vomiting,  sometimes  diarrhoea,  but  constipation  is 
more  common. 

Perhaps  the  most  distressing  of  all  the  symptoms  are  the  haemor- 
rhages. Attacks  of  epistaxis  are  common.  Bleeding  from  the  gums 
is  another  very  common  feature.  A  slight  persistent  oozing  from 
different  points  in  the  alveolar  margin  of  the  gums  takes  place.  Pieces 
of  clot  get  entangled  in  the  teeth.  Should  the  bleeding  stop,  the 
attendants  are  content  to  leave  well  alone  rather  than  attempt  their 
removal,  so  that  the  mouth  becomes  very  foul,  the  tongue  being  dry 
and  covered  with  sordes.  Bleeding  may  be  arrested  at  one  point  only 
to  break  out  at  another,  and  if  perchance  the  gums  stop  bleeding  for  a 
time,  the  interval  is  often  occupied  by  epistaxis. 

The  nose  is  often  blocked,  so  that  patients  breathe  through  the 
mouth.  A  diphtheritic  membrane  may  form  on  the  gums  or  cheeks. 
There  may  be  local  necroses  and  ulceration.  The  teeth  loosen,  and  the 
condition  of  the  mouth  resembles  that  seen  in  scurvy.  Haematemesis 
and  haematuria  are  less  common  forms  of  haemorrhage.  Bleeding  from 
any  mucous  membrane  may  take  place.     Bleeding  may  cease  some  days 


LEUCOCYTILEMIA— LEUKAEMIA  203 

before  death,  and  occasionally  deafness  may  come  on  from  haemorrhage 
into  the  inner  ear.  In  one  of  our  cases  blindness  in  both  eyes  occurred 
from  haemorrhage  into  the  vitreous. 

Purpuric  spots  are  common.  There  may  be  difficulty  in  getting 
bleeding  from  a  slight  skin  puncture  to  stop.  A  hypodermic  injection 
may  lead  to  the  formation  of  a  hematoma,  and  a  slight  knock  may 
be  followed  by  a  large  ecchymosis.  Hemorrhagic  retinitis  sometimes 
occurs,  and  cerebral  haemorrhage  is  an  occasional  termination.  The 
urine  shows  no  constant  changes  beyond  those  associated  with  fever. 
There  is  often  an  increase  in  the  output  of  uric  acid,  and  albuminuria 
may  appear.  Paralysis  of  cranial  nerves  from  lymphoid  infiltration  or 
growth  about  their  sheaths  is  sometimes  met  with. 

The  rapid  anaemia  causes  the  usual  dilatation  of  the  heart  with 
systolic  murmurs,  and  oedema  of  the  feet  and  legs  often  appears  towards 
the  end.  The  pulse  is  rapid,  of  poor  force,  and  low  pressure.  Mental 
symptoms  are  not  uncommon.  The  patient  may  either  become  quiet, 
stupid  and  comatose,  may  merely  wander  in  his  talk,  or  may  be 
talkatively  delirious.  He  is  too  weak  to  be  violent.  The  end  may  be 
hastened  by  intercurrent  diseases,  especially  by  pneumonia  and  pleurisy. 
In  one  case  the  occurrence  of  an  extensive  dry  pneumococcal  pleurisy 
was  the  first  thing  which  drew  attention  to  the  patient's  condition. 

(b)  Chronic  Lymphatic  Leukaemia. — This  form  is  much  less  common 
than  acute  lymphaemia.  The  onset  is  always  insidious.  As  a  rule 
enlargement  of  groups  of  glands  takes  place  and  increases,  sometimes  to 
an  enormous  extent.  Almost  every  gland  in  the  body  may  be  increased 
in  size,  and  individual  glands  may  be  as  large  as  hens'  eggs.  Cases 
without  glandular  enlargement,  however,  have  occurred.  The  spleen 
enlarges  and  reaches  an  enormous  size.  The  liver,  too,  increases  in  size. 
For  long  there  may  be  no  other  symptoms.  The  functions  of  various 
organs  may  be  interfered  with  from  the  lymphatic  invasion.  Great 
general  weakness  and  anaemia  eventually  supervene,  and  the  patient 
becomes  breathless  and  dyspnoeic.  Lymphomata  sometimes  develop  in 
the  skin.  They  may  be  small  tubercles,  or  may  be  as  large  as  a  bean. 
The  larger  nodules  are  most  common  on  the  face.  The  tumours  grow 
very  slowly  and  have  little  tendency  to  break  down.  Bence  Jones' 
proteinuria  has  been  recorded  in  a  few  cases.1 

Many  patients  go  about  their  usual  work  apparently  little  disturbed 
in  spite  of  high  leucocyte  counts,  great  glandular  and  splenic  enlarge- 
ment, and  anaemia,  until  the  final  breakdown  comes  which  carries  them 
1  Boggs  and  Guthrie,  Johns  Hopkins  Hosp.  Bulletin,  December  1913. 


204  LEUCOCYTH^MIA— LEUKEMIA 

off  in  a  few  weeks.  The  final  stage  may  be  one  of  anaemia  and  cachexia, 
but  many  cases  end  up  with  the  symptoms  usually  associated  with  an 
acute  attack. 

Other  cases  die  from  the  effects  of  pressure  by  the  enlarged 
glands,  and  sometimes  the  end  is  brought  about  by  an  intercurrent 
affection. 

In  rare  cases  there  is  remission  with  or  without  treatment.  These 
are  so  uncommon  that  the  following  case  is  worth  detailing  : — The 
patient  was  a  man  of  nearly  seventy,  whom  we  saw  for  the  first  time  in 
November  1910.  He  had  been  in  excellent  health  till  the  end  of  July 
in  that  year ;  then  he  became  gradually  paler  and  progressively  weaker. 
Two  counts  made  a  fortnight  before  we  saw  him  gave  the  same  result — 
reds,  2,500,000;  haemoglobin,  50  per  cent.;  colour  index,  1;  whites,  54,000, 
over  90  per  cent,  of  which  were  lymphocytes.  There  were  some 
nucleated  reds  in  the  first  set  of  films  (after  a  journey),  not  in  the 
second.  ~No  lymph  glands  were  enlarged,  liver  was  normal  in  size, 
spleen  just  palpable  at  the  edge  of  the  ribs.  There  had  been  no 
haemorrhage.  Our  count  was  reds,  1,500,000;  haemoglobin,  33;  colour 
index,  1-1;  whites,  135,000;  lymphocytes,  over  90  per  cent.;  no  nucleated 
reds.  We  feared  that  he  would  go  steadily  downhill,  and  as  he  wished 
to  return  to  his  home  in  the  country,  allowed  him  to  do  so,  with  direc- 
tions to  take  arsenic  and  naphthalene  tetrachloride.  He  improved 
steadily,  but  gave  up  the  arsenic,  of  which  he  had  never  taken  more  than 
5  tt\_  t.i.d.,  in  April  1911,  as  he  had  a  very  severe  herpes  of  the  right  side 
of  the  head  and  neck  and  inside  the  mouth.  The  other  drug  was  con- 
tinued steadily.  We  saw  him  again  in  October  1911,  when  he  looked 
practically  well,  and  complained  of  nothing  except  some  neuralgia  per- 
sisting after  the  herpes.  His  heart  sounds  were  normal;  the  spleen  was 
normal  in  size ;  no  glands  could  be  felt  anywhere.  The  count  was  reds, 
4,240,000  ;  haemoglobin,  75  per  cent. ;  colour  index,  0*9  ;  whites,  7300,  of 
which  lymphocytes  were  75  per  cent.,  polymorphs  25  per  cent.  The 
lymphocytes  were  all  either  small  or  medium  in  size ;  there  were  none 
of  the  "  dropsical "  cells  which  were  present  before. 

The  Blood  Changes. — In  a  typical  case  the  blood  is  pale  and 
watery.  Coagulation  time  in  vitro  is  apparently  not  diminished.  There 
is  always  anaemia.  In  the  acute  cases,  and  particularly  in  the  haemor- 
rhagic  forms,  the  anaemia  may  be  extreme.  In  one  of  our  cases  the  red 
cells  fell  from  4,000,000  to  660,000  per  c.mm.  in  ten  days.  The  red 
cells  show  the  ordinary  features  fouud  in  secondary  anaemia,  but  in 


Plate  X. — Acute  Lymphatic  Leukttcmia  (Jennet's  Stain). 


A.  G  ,  fecit. 


LEUCOCYTH^EMIA— LEUKAEMIA  205 

most  advanced  cases  there  is  a  disturbance  of  the  marrow  leading  to  the 
output  of  numerous  nucleated  red  cells  into  the  circulation. 

Normoblasts  are  sometimes  found  in  large  numbers,  even  at  an  early 
stage.  There  may  be  500  per  c.mm.  when  the  number  of  red  cells  has 
fallen  to  4,000,000.  In  the  later  stages  megaloblasts  are  also  present 
in  large  numbers,  especially  in  young  subjects.  The  haemoglobin  is  of 
course  also  greatly  diminished,  and  the  colour  index  is  low  in  the  early 
stages  of  the  disease.  As  the  anaemia  becomes  greater  it  may  rise  ao-ain, 
reaching  unity  or  even  exceeding  it.  This  is  always  associated  with  a 
megaloblastic  blood-picture. 

White  Cells. — The  leucocyte  count  is  almost  always  increased.  The 
numbers  reached  in  the  chronic  cases  are  much  higher  than  those  found 
in  the  acute  cases.  In  chronic  lymphsemia  counts  of  over  500,000  are 
not  unknown,  but  in  the  acute  cases  the  numbers  seldom  exceed  150,000 
per  c.mm. 

Much  lower  counts,  however,  are  the  rule  in  both.  Cabot  puts  the 
average  in  the  chronic  cases  at  100,000.  We  should  be  inclined  to  make 
it  rather  higher,  say,  150,000.  It  is  difficult  to  name  an  average  for  the 
acute  cases,  for  many  of  the  "acute"  cases  published  have  really  been 
merely  the  acute  terminations  of  chronic  cases,  and  in  them  the  count 
is  naturally  high.  Any  "  acute "  case  in  literature  which  has  shown 
marked  enlargement  of  the  spleen  should  be  regarded  with  suspicion. 
In  the  really  acute  cases  the  count  is  often  surprisingly  low.  We  have 
several  times  made  the  diagnosis  with  counts  as  low  as  10,000,  and  once 
with  a  count  of  6800,  and  have  seen  these  cases  die  with  counts  of 
17,500,  19,000,  20,000,  and  25,000.  In  one  remarkable  case,  which  was 
complicated  with  tuberculosis,  the  count  remained  at  about  4000  for 
several  weeks.  All  these  cases  showed  over  90  per  cent,  of  lymphocytes, 
usually  about  98  per  cent. 

The  increased  white  cell  count  is  entirely  due  to  an  increase  in 
lymphocytes,  either  large  or  small.  It  has  been  thought  that  the 
type  of  the  disease  could  be  predicted  from  the  kind  of  lymphocyte 
preponderating  in  the  blood.  Large  lymphocytes  were  supposed  to  be 
characteristic  of  acute  cases  and  small  lymphocytes  of  chronic.  From 
the  subjoined  table,  compiled  from  a  set  of  cases  occurring  in  a  given 
time,  and  not  otherwise  selected,  it  will  be  seen  that  there  is  absolutely 
no  general  rule  in  either  acute  or  chronic  cases.  In  either  class  of  case 
the  large  or  small  cells  may  be  in  excess  ;  they  may  be  equal  in  amount, 
or  there  may  be  so  many  transitional  forms  between  the  two  that  it  may 
be  impossible  to  make  an  accurate  differential  count.     The  only  point 


206 


LEUCOCYTH^MIA— LEUKAEMIA 


about  the  acute  cases  is  that  they  sometimes  seem  to  lead  to  extrava- 
gance in  one  direction  or  another.  In  no  chronic  case  have  we  seen  such 
large  dropsical  cells  nor  such  small  cells  as  in  some  of  the  acute  ones. 


Acute — 

Large. 

Small. 

Remarks. 

M.,  set.  13    . 

Gradations  so  numerous  that 
it  was  impossible  to  make 
accurate  count.  Most  were 
fairly  large. 

M,    „    61     .         .        . 

1 

99 

Unusually  small  lymphocytes. 

M.,   „    19    .         .         . 

54 

46 

Many  doubtful  and  many 
burst. 

F,    „    15     .         .         . 

22 

35 

43  per  cent,  intermediate. 

M.,    „      5     . 

16 

84 

M,    „    17     .         .         . 

76 

24 

Many  of  large  swollen  and 
dropsical. 

F.,    „     6    .         .         . 

98 

2 

„  „  even  more 
marked. 

M.,   „    13    .         .         . 

34 

66 

M.,   „    18    . 

80 

20 

Subacute — 

M.,  set.  22    . 

75 

25 

M.,    „    22    .         .         . 

Impossible  to  distinguish,  so 
many  transitions. 

M.,    „    30    . 

31 

69 

Many  intermediate. 

Chronic — 

M.,  set.  70    .        . 

31 

69 

jj                 )> 

F.,     „    42    . 

83 

17 

M.,   „    40    . 

60 

40 

M.,    „    56    . 

90 

10 

...                    ... 

M.,    „    53    . 

58 

42 

The  percentage  of  lymphocytes  is  usually  over  90  and  is  not  in- 
frequently 99.  Occasionally  the  lymphocytes  (usually  large)  show 
marked  vacuolation,  usually  in  the  cytoplasm,  but  sometimes  in  the 
nucleus  also.  The  "  dropsical "  cells  have  already  been  referred  to. 
They  are  more  numerous  in  the  acute  cases,  and  vary  greatly  in 
number.  In  stained  films  they  are  large  cells  whose  cell-body  and 
nucleus  are  pale,  and  hardly  take  up  any  stain.  The  nucleus  often 
seems  to  merge  indefinitely  into  the  cell-body.  These  cells  are  easily 
destroyed  in  the  making  of  films,  and  nothing  may  be  left  of  them  but 
a  pale  irregular  nucleus.     They  are  obviously  degenerated  forms. 

The  actual  number  of  polymorphs  may  be  about  normal  but  is 
often  somewhat  reduced.  A  few  myelocytes  are  always  present  in 
the  acute  cases,  in  small  numbers  to  begin  with,  but  becoming  more 
numerous. 


Plate  XL — Acute  Lymphatic  Leukemia  (Leisliman'.s  Stain). 

This  stain  demonstrates  azurophil  granules  in  some  of  the  large  lymphocytes  (a). 
('/)  A  collection  of  blood-plates  showing  central  chromatin  staining. 
(c)  A  normoblast. 


A.  G.,  fecit. 


LEUCOCYTILEMIA— LEUKAEMIA  207 

Eosinophils  are  always  diminished.  In  one  case  we  saw  a  con- 
siderable increase  in  the  number  of  basophils.  Blood-plates  are 
always  diminished. 

Diagnosis. — Judging  from  the  large  number  of  cases  we  have  seen 
diagnosed  for  the  first  time  in  the  post-mortem  room,  and  the  number 
of  times  we  have  seen  cases  wrongly  diagnosed,  we  have  no  hesitation 
in  saying  that  acute  lymphatic  leukaemia  is  a  much  more  common 
condition  than  is  generally  supposed.  The  diagnosis  is  perfectly  simple 
if  the  blood  be  examined.  It  may  be  impossible  if  the  condition  of  the 
blood  is  unknown. 

The  important  point  to  recognise  is  that  the  excess  of  leucocytes 
to  begin  with  may  not  be  very  great ;  but  if  there  be  a  definite  excess, 
and  the  percentage  of  lymphocytes  be  over  85,  there  can  be  little  doubt 
of  the  nature  of  the  case.  Stress  is  to  be  laid  rather  on  the  lympho- 
cyte percentage  than  on  the  total  count.  We  have  seen  a  somewhat 
similar  blood-picture  in  a  few  cases  of  tuberculosis,  though  never  with 
quite  so  high  a  lymphocyte  percentage,  and  if  a  real  difficulty  arose 
in  this  direction  a  tuberculin  test  might  be  applied.  The  possibility 
of  the  existence  of  a  tuberculous  nodule  in  a  case  of  leukaemia  must  be 
remembered.  The  course  of  the  two  conditions  is  so  vastly  different 
that  in  any  case  the  doubt  would  not  be  of  long  duration.  In  chronic 
lymphatic  leukaemia  the  number  of  lymphocytes  in  the  blood  is  so  great 
that  the  diagnosis  need  never  be  in  doubt. 

Intercurrent  affections  may  lower  the  total  count,  but  the  percent- 
age of  lymphocytes  remains  high.  In  the  rarer  cases  in  which  a  poly- 
morph leukocytosis  is  superadded  to  the  lymphocytosis  the  percentage 
of  lymphocytes  usually  remains  above  75.  The  same  holds  for  remis- 
sions. Even  though  the  count  returns  to  normal  the  lymphocytes 
will  remain  at  about  75  per  cent. 

Prognosis. — The  disease  is  uniformly  fatal.  The  chronic  cases  have 
a  somewhat  precarious  expectation  of  a  few  years  of  life,  but  many  are 
dead  within  twelve  months.  Eemissions  may,  however,  occur,  with 
complete  loss  of  symptoms,  diminution  of  the  enlarged  spleen,  liver  and 
glands,  normal  red  count  and  haemoglobin,  normal  white  count,  but  in 
our  experience  the  lymphocyte  percentage  always  remains  high. 

The  acute  cases  vary  considerably,  but  within  narrow  limits.  Some 
cases  die  within  two  days  of  an  initial  haemorrhage.  Perhaps  most 
commonly  the  duration  of  the  disease  after  it  has  attracted  attention 


208  LEUCOCYTH^EMIA— LEUKAEMIA 

is  from  a  fortnight  to  a  month.  A  few  cases  live  for  from  three  to  six 
months.  Very  rarely  cases  begin  acutely  and  become  chronic.  Eupture 
of  the  spleen  is  a  rare  complication. 

Serious  symptoms  are  sudden  onset,  high  temperature,  haemorrhages, 
and  rapidly  advancing  anaemia.  A  falling  leucocyte  count  does  not 
necessarily  indicate  any  amelioration  in  the  patient's  condition. 

Treatment. — In  acute  lymphaemia  the  general  treatment  is  that  of 
any  febrile  condition.  Special  care  is  required  to  avoid  any  slight 
injury  which  might  lead  to  bruising.  The  most  urgent  symptom  is 
generally  haemorrhage,  and  sometimes  the  medical  attendant  may  arrive 
at  the  end  of  his  resources  without  being  able  to  control  it.  Adrenalin 
does  not  seem  to  do  much  good.  Although  it  is  messy  and  leaves 
an  ugly  black  clot,  we  have  found  the  liquor  ferri  perchloridi  fortior 
specially  efficacious  in  controlling  bleeding  from  the  gums  and  anterior 
part  of  the  nose. 

No  known  drug  has  the  slightest  influence  on  the  course  of  the  disease. 
X-rays  certainly  do  harm  in  the  acute  cases ;  they  seem  to  exercise  a 
toxic  influence.  The  temperature  rises,  and  the  disease  seems  to  run 
its  course  more  rapidly  when  they  are  used. 

The  chronic  cases  should  lead  a  healthy  outdoor  life  as  long  as 
possible.  Arsenic  and  X-rays  should  be  tried  as  in  chronic  myelo- 
cythaemia,  and  are  sometimes  useful.  In  a  recent  chronic  case 
symptomatic  improvement  coincided  with  the  use  of  naphthalene 
tetrachloride  in  5  to  10  grain  doses. 

Benzol  administered  in  the  form  of  5  tt\_  capsules,  along  with  5  TT^ 
of  olive  oil,  has  been  given  in  doses  up  to  20  1Tb  three  times  a  clay  in  a 
small  number  of  cases,  and  a  measure  of  improvement  has  followed 
in  a  few  instances.  In  others  no  benefit  has  been  obtained,  and  in 
one  instance  necrotic  areas  found  in  the  liver  after  death  were 
attributed  to  its  administration. 

Thorium  X  has  also  been  tried,  but  its  use  has  no  very  enthusiastic 
advocate. 


CHAPTER  XXI 
LEUCOCYTEkEMIA— {continued) 

2.  Myelocytilemia 

Etiology. — The  disease  may  occur  at  almost  any  age,  but  it  is  very 
much  more  common  between  the  ages  of  twenty  and  fifty  than  at  any 
other  time  of  life.  A  small  number  of  cases  have  occurred  in  infancy, 
and  a  few  congenital  cases  have  been  recorded  (Chap.  XXVII.).  It  is 
more  frequent  in  males  than  females,  the  proportion  being  approxi- 
mately two  to  one.  Overwork,  worry,  unsuitable  surroundings  and  bad 
food  are  among  the  factors  which  have  been  supposed  to  be  causal.  All 
such  suggestions  are  mere  conjecture. 

Morbid  Anatomy  and  Histology. — The  general  appearances  are 
pretty  much  the  same  as  those  of  lymphatic  leukaemia.  The  alimentary 
canal  seldom  shows  any  gross  lesion,  and  the  microscopic  changes  are 
but  slight.  An  increase  of  white  cells  in  the  submucosa  is  the  main 
feature.     Intestinal  ulcers  have  been  noticed  in  a  few  instances. 

Liver. — The  liver  is  considerably  enlarged  in  a  fair  proportion  of  cases. 
This  is  mainly  due  to  a  packing  of  the  portal  spaces  and  hepatic  capil- 
laries with  leucocytes.  Sometimes  large  areas  of  liver  tissue  may  be 
rendered  unrecognisable  by  the  capillary  engorgement,  and  the  cells 
may  be  squeezed  into  thin  strands,  or  may  have  altogether  disappeared. 
The  cells  present  correspond  roughly  to  those  in  the  blood.  Normo- 
blasts are  often  seen  in  the  capillaries.  Giant  cells  of  bone-marrow 
type  are  sometimes  present.  Large  phagocytes  ingesting  red  and 
white  cells  are  present  in  a  majority  of  the  cases.  Pigment  is  always 
present  in  moderate  amount,  and  often  gives  the  iron  reaction. 

Kidneys. — Catarrhal  changes  are  often  present.  Leucocyte  infiltra- 
tion, in  some  cases  destroying  the  tubular  structure,  is  often  found. 
Giant  cells  and  pigment  are  frequently  present.  Deposits  of  uric  acid 
are  by  no  means  common. 

Spleen. — In  a  few  cases  the  enlargement  of   the  spleen  is  slight ; 

209  14 


210  LEUCOCYTELEMIA 

usually  it  is  massive.  The  Malpighian  bodies  are  small  and  usually 
atrophied.  The  pulp  is  packed  with  cells  corresponding  to  those  in 
the  blood.  There  may  be  an  increase  of  fibrous  tissue.  Giant  cells, 
phagocytes,  and  pigmentary  changes  are  found. 

The  Lymphatic  Glands. — Glandular  enlargement  is  not  constant 
and  the  groups  affected  vary  greatly.  The  histological  change  is  an 
invasion  with  myelocytes,  lymphocytes,  and  the  other  forms  in  the 
circulating  blood.  Structure  is  seldom  obliterated  so  completely  as 
in  the  case  of  lymphatic  leuksemia,  and  many  glands  appear  normal. 
Haimolymph  glands  are  generally  more  invaded  than  the  lymph  glands 
and  may  show  pigmentary  changes. 

The,  Bone-Marrow. — The  bone-marrow  throughout  the  body  has  a 
pink  colour  and  is  soft  in  consistency  though  moderately  tenacious. 
It  is  definitely  myelocytic  in  character.  The  fat  in  the  shafts  of  the 
long  bones  is  in  large  measure  replaced  by  hemopoietic  cells.  Myelo- 
cytes are  usually  most  in  evidence,  next  to  them  red  cells.  In  some 
cases  there  are  large  numbers  of  eosinophils,  and  there  is  always  a  fair 
number  of  large  lymphocytes.  Giant  cells  are  scanty.  Phagocytic 
cells  are  not  constant.     Pigmentary  changes  are  sometimes  present. 

The  Blood. — Macroscopically  the  blood  seen  post-mortem  presents 
a  remarkable  appearance.  Large  greenish-yellow  clots  may.  be  found 
in  the  heart  and  large  vessels,  and  the  vessels  in  some  cases  may 
contain  a  yellowish-white  fluid  resembling  pus.  In  other  cases  the 
vessels  present  for  the  most  part  the  ordinary  appearances,  but  whitish 
clots  of  small  size  may  be  seen  here  and  there. 

Pathology. — The  disease  consists  of  an  excessive  production  of 
leucocytes  of  the  granular  series  and  lymphocytes  (myeloblasts)  in 
the  bone  -  marrow.  These  cells  pass  into  the  blood  -  stream  and 
invade  the  various  organs.  The  spleen,  in  virtue  of  its  function  of 
dealing  with  effete  cells  in  the  blood,  has  to  bear  the  brunt  of  the 
invasion,  hence  the  special  enlargement  of  that  organ.  Since  the 
number  of  leucocytes  in  the  blood  is  usually  much  greater  in  myelo- 
cythEemia  than  in  lymphatic  leuksemia,  the  spleen  is  usually  very  much 
larger  in  the  former.  Nothing  certain  is  known  regarding  patho- 
genesis. Alleged  blood  parasites  have  failed  to  carry  conviction. 
Injections  of  leukemic  blood  into  animals  and  even  into  human 
subjects  suffering  from  carcinoma  have  failed  or  been  inconclusive. 
The  disease  occurs  in  dogs,  cats,  horses,  cattle,  sheep,  goats,  and  rats, 
and  a  somewhat  analogous  condition  is  found  in  fowls.     Injections  of 


LEUCOCYTELEMIA  211 

blood  from  a  leukemic  dog  into  healthy  dogs  have  failed  to  transmit 
the  disease. 

For  very  much  the  same  reasons  as  those  given  in  connection  with 
lymphatic  leukaemia  we  regard  myelocythaemia  as  a  useless  overgrowth 
of  marrow  cells,  possibly  due  to  the  disturbance  of  the  mechanism 
governing  cell  production — something  akin  to  sarcomatosis.  The  origin 
of  the  conditions  may  differ,  since  a  sarcoma  always  begins  locally, 
while  leukaemia  is  probably  not  a  localised  process  in  the  same  strict 
sense  in  the  beginning,  though  possibly  the  great  mobility  of  the  tissue 
involved  may  account  for  the  early  diffusion  of  the  process.  As 
the  elements  involved  are  mainly  granular  cells  in  myelocythaemia, 
and  as  these  are  more  highly  differentiated  than  the  lymphocytes,  the 
disease  is  less  malignant,  and  therefore  in  the  great  majority  of  cases 
runs  a  more  chronic  course  than  lymphatic  leukaemia. 

Symptoms. — (a)  Chronic  Myelocythcemia. — The  disease  is  usually 
well  developed  before  the  patient  has  any  idea  of  its  existence. 
Attention  is  often  drawn  to  the  condition  by  some  comparatively 
insignificant  symptom,  such  as  epistaxis,  excessive  bleeding  after  tooth 
extraction,  or  a  pain  in  the  side.  One  of  our  cases  was  a  medical 
practitioner,  whose  first  intimation  of  illness  was  the  accidental  dis- 
covery of  an  enlarged  spleen.  His  blood  showed  200,000  leucocytes 
per  c.mm.  and  a  large  number  of  normoblasts. 

Even  after  such  a  blood  finding  there  may  be  complete  absence  of 
subjective  symptoms  for  months  or  years,  and  the  general  nutrition  of 
the  patient  remains  good.  Gradually  increasing  weakness  may  be  com- 
plained of.  Pain  in  the  side  from  perisplenitis,  loss  of  appetite,  and 
pain  and  tenderness  of  the  long  bones  may  be  complained  of.  The 
patient  may  begin  to  lose  flesh.  The  temperature  shows  variations 
which  baffle  explanation.  Some  cases  are  afebrile  from  first  to  last, 
others  may  show  a  temperature  of  from  100°  to  103°  for  a  week  or  two 
at  a  time,  and  other  cases  may  show  a  swinging  temperature  through- 
out the  whole  course  of  the  illness.  Anorexia,  nausea,  and  thirst  may 
be  found.  Attacks  of  diarrhoea  are  not  uncommon,  and  may  prove 
exceedingly  persistent.  Stomatitis  is  sometimes  found,  especially  in 
cases  with  bleeding  from  the  gums.  The  liver  is  frequently  somewhat 
enlarged,  but  sometimes  appears  to  be  small  because  of  abdominal  dis- 
tension.    Ascites  may  occur  as  a  terminal  symptom. 

The  spleen  is  always  enlarged  to  some  extent  and  usually  very 
greatly.     It  may  appear  to  rest  on  the  left  pelvic  brim.     The  abdomen 


212  LEUCOCYTH^EMIA 

in  such  cases  is  greatly  distorted.  The  spleen  is  usually  hard  and  the 
notches  along  the  border  are  easily  palpated.  Earely  the  spleen  is 
soft  in  consistency.  Its  size  sometimes  undergoes  alterations.  Under 
the  influence  of  an  intercurrent  disease  it  may  become  small,  and 
X-rays  have  the  effect  of  causing  a  material  reduction  in  size  in 
most  cases.  In  a  recent  case  the  spleen  was  mobile,  though  very  large, 
and  was  sometimes  found  in  the  centre  of  the  abdomen,  sometimes  at 
the  left  side,  and  occasionally  in  a  nearly  transverse  position.  In  some 
cases  the  spleen  is  prevented  from  enlarging  in  a  downward  direction 
owing  to  the  existence  of  a  strong  costo-colic  fold  of  peritoneum.  In 
such  instances  splenic  dulness  extends  upwards  towards  the  thorax. 

The  lymphatic  glands  show  uncertain  and  very  irregular  enlarge- 
ment. It  is  rarely  massive.  The  inguinal  and  axillary  are  perhaps 
the  most  commonly  involved.  Pressure  symptoms  sometimes  arise 
from  the  enlargement  of  mediastinal,  abdominal,  or  pelvic  glands. 

There  may  be  cardiac  murmurs  and  the  symptoms  associated  with 
anaemia  as  the  disease  progresses.  Distension  of  superficial  abdominal 
veins  may  be  noted  when  there  is  much  abdominal  distension.  In  the 
late  stages  there  is  often  oedema  of  the  lower  limbs.  Bronchitis  with 
cough  is  not  uncommon.  The  sputum  may  contain  a  large  number  of 
eosinophils.  Warthin  describes  a  case  which  died  from  symptoms  of 
oedema  of  the  glottis.  Post-mortem  sufficient  leukaemia  infiltration 
of  the  larynx  to  cause  stenosis  was  found.  Pleuritic  effusions  may 
occur.  Serous  effusions  show  the  usual  cellular  content  determined 
by  their  cause,  but  hemorrhagic  effusions  contain  the  same  kinds  of 
cells  as  are  present  in  the  blood.  A  case  with  chylous  ascites  has  been 
reported.  The  chief  cause  of  the  milky  appearance  of  the  fluid  was  the 
presence  of  myelocytes.  The  skin  is  dry  and  pale.  Lymphomatous 
tumours  occasionally  occur.  Petechias  are  not  uncommon.  The  urine 
shows  no  special  peculiarities.  Deposits  of  uric  acid  may  occur,  but 
are  not  constant,  and  have  no  relation  to  the  number  of  leucocytes 
in  the  blood.  There  is  always  a  heavy  deposit  of  uric  acid  in  the 
first  few  days  after  X-ray  treatment  is  begun,  presumably  from  the 
destruction  of  leucocytes. 

Priapism  is  complained  of  in  some  cases.  This  may  be  due  to 
thrombosis  of  the  corpora  cavernosa,  and  may  call  for  relief  by  incision. 
The  condition  may  persist  after  death.  Suppression  of  the  menses 
occurs  in  advanced  cases.  Menorrhagia  is  uncommon.  Leukemic , 
women  have  given  birth  to  healthy  children,  without  apparent  aggra- 
vation of  their  symptoms,  but  death  has  occurred  from  haemorrhage 


LEUCOCYTH.EMIA  213 

after  abortion.  Symptoms  referable  to  the  eye  are  not  common  in  this 
form  of  leukaemia.  Tinnitus,  vertigo  and  deafness,  sometimes  from 
hemorrhage  into  the  middle  or  internal  ear,  are  more  frequently  met 
with.  Transverse  myelitis,  nerve  infiltration,  and  hemorrhages  have 
been  found  in  a  small  number  of  cases.1  An  association  with  osteo- 
sclerosis has  been  recorded  in  four  cases.2  The  terminal  stage  does 
not  differ  as  regards  the  symptoms  from  the  terminal  stage  of 
lymphocytheinia. 

(b)  Acute  Myelocythcemia. — This  condition  is  very  rare.  Hirschfeld, 
in  1904,  could  find  records  of  only  six  undoubted  cases,  and  the  number 
now  on  record  is-  still  very  small.  (We  refer,  of  course,  to  cases  in 
which  the  preponderating  cells  are  myelocytes  with  granules.  A  very 
considerable  number  of  myeloblast  or  "  lymphoidocyte "  cases  have 
been  reported  as  "  acute  myeloid  "  leukemia.  As  we  explained  in  the 
section  on  Classification  we  prefer,  on  clinical  as  distinguished  from 
cytological  grounds,  to  refer  such  cases  to  the  lymphatic  groups.) 
Acute  myelocythemia  has  occurred  at  ages  between  infancy  and  sixty- 
eight.  There  is  no  difference  in  symptoms  between  this  and  the  chronic 
form,  except  their  greater  severity  and  the  more  rapid  incidence  of 
anemia.  The  blood-picture  shows  variations  of  the  same  kind  that 
occur  in  the  more  common  form. 

The  Blood  Changes.  —  The  naked-eye  appearance  of  the  blood 
has  none  of  the  striking  characters  which  are  so  conspicuous  after 
death.  The  blood  may  look  almost  normal,  but  is  sometimes  more 
opaque  than  usual.  A  point  often  noticed  is  the  difficulty  in  getting 
films  to  spread  evenly,  owing  to  the  large  excess  of  white  cells. 

Cases  seen  reasonably  early  show  no  signs  of  anemia,  and  the  shape, 
size,  and  staining  reactions  of  the  red  corpuscles  are  not  altered. 

From  the  outset,  however,  nucleated  red  cells  in  the  blood  are  a 
conspicuous  feature  of  the  disease  in  the  great  majority  of  cases.  The\ 
are  usually  numerous  enough  to  be  found  without  any  difficulty,  but 
sometimes  they  are  not  to  be  seen.  ^Normoblasts  preponderate  in  the 
majority  of  cases,  but  megaloblasts  may  also  be  numerous.  The  greatest 
numbers  we  have  seen  when  the  patient  first  came  under  observation 
were:  normoblasts,  35,000  per  c.nim. ;  megaloblasts,  17,000.  In  only  one 
case  (a  child)  have  we  seen  megaloblasts  in  the  majority.     The  numbers 

1  Baudouin  and  Parturier,  Revue  Neurologique,  1910. 

2  Goodall,  Eclin.  Med.  Journ.,  1912,  and  Trans.  Med.  Cliirurg.  Soc.  Edin,,  xxxi. 
1911-12. 


214  LEUCOCYTELEMIA 

were  :  megaloblasts,  15,000  per  c.mm. ;  normoblasts,  2500.  In  only  one 
case  have  we  failed  to  find  normoblasts  throughout  the  whole  course 
of  the  illness.  We  have  seen  as  many  as  7  normoblasts  to  every  300 
white  cells  in  a  man  who  was  doing  a  full  day's  work  as  a  labourer,  and 
in  whom  the  disease  was  discovered  accidentally. 

In  the  later  stages  anaemic  symptoms  supervene,  and  the  usual 
picture  of  secondary  anaemia  is  grafted  on  the  myelocytic  blood. 
Haemoglobin  remains  proportional  to  the  number  of  red  cells  till 
anaemia  supervenes,  and  then  the  colour  index  tends  to  become  low. 
In  cases  with  a  very  high  white  count  it  is  difficult  to  estimate 
haemoglobin  accurately  by  any  of  the  methods  which  depend  on  trans- 
mitted light,  for  the  large  number  of  leucocytes  renders  the  diluted 
blood  more  or  less  opaque. 

White  Cells. — The  number  of  white  cells  is,  as  a  rule,  greatly 
increased.  In  no  other  condition  are  such  high  counts  ever  obtained. 
The  usual  limits  are  from  200,000  to  500,000  per  c.mm.,  but  may  reach 
1,000,000  or  more.  During  remissions  and  during  intercurrent  affec- 
tions the  leucocyte  count  may  fall  to  a  low  figure,  but  even  in  these 
cases  abnormal  cells  are  apt  to  persist. 

The  chief  feature  of  the  blood  is  the  large  number  of  myelocytes 
which  it  contains.  All  varieties — neutrophil,  eosinophil,  and  basophil 
— are  represented.  In  addition  to  this  essential  feature  all  the  varieties 
of  normal  leucocytes  are  increased.  This  is  specially  well  illustrated  in 
the  case  of  the  lymphocytes.  If  we  take  half  a  dozen  cases  at  random 
the  totals  work  out  in  this  way — 

Total  counts  .  .         412,000     400,000     8000     116,500     136,000     451,800 

Total  lymphocytes .  .  41,200       16,200     2240         5,825       14,820       22,590 

Lymphocyte  percentage  10  4  28  5  12  5 

The  overwhelming  number  of  polymorphs  and  myelocytes  generally 
results  in  the  percentage  numbers  of  the  others  being  low,  but  their 
total  numbers  are  always  increased. 

In  most  cases  large  lymphocytes  are  a  striking  feature  in  films. 
These  are  often  specially  large  and  their  protoplasm  is  deeply  basophil, 
and  one  is  left  in  little  doubt  that  these  cells  are  really  myeloblasts. 
But  when  differential  counts  are  made,  so  many  forms  are  found  which 
appear  intermediate  between  these  and  typical  large  lymphocytes  that 
it  is  impossible  to  know  where  to  draw  the  line  of  differentiation,  or  at 
least  to  draw  it  so  that  the  separation  would  have  any  meaning  to  any 
one  but  the  individual  observer.     In  no  other  disease  is  the  proportion 


Plate  XLI. — Myelocyth^emia  (Jenner's  Stain). 

The  most  numerous  white  cells  are  neutrophil  myelocytes.  There  are  two  eosinophil  myelocytes, 
one  with  some  unripe  (basophil)  granules.  The  remaining  white  cells  are  four  lymphocytes, 
five  polymorphonuclear  neutrophils,  one  eosinophil  and  one  basophil. 

There  are  two  normoblasts. 


A.   G.,  Jertf. 


LEUCOCYTH^MIA 


215 


and  number  of  basophils  so  constantly  high.  Tomaszewski 1  has  recorded 
a  case  with  303,000  leucocytes  per  cram.  Of  these  37  per  cent,  or 
112,110  per  c.mm.  were  basophils. 

While  the  blood-picture  in  myelocythEemia  is  a  very  definite  one, 
there  are  remarkable  differences  between  individual  cases.  One  may 
appear  overwhelmingly  melocytic,  another  may  show  a  specially  large 
number  of  eosinophils,  and  so  on.  This  point  may  be  best  illustrated 
by  the  following  table  showing  the  result  of  enumeration  and  differen- 
tial counts  of  the  leucocytes  made  when  the  patient  first  came  under 
observation  : — 


Per  300 

No. 

Sex. 

Age. 

a 
o 

s 

o 

>> 

o 
ft 
S 

bo 

(3 
t-1 

u 

OS 

<x> 
"3 

a 
o 

a 
o 

03 
60 
f-i 

a 
h3 

J-3 
O 

o 

S 
3 

02 

a. 

o 
p 

o 
o 

-^ 

o 

o 

a 
o 

o 

"ft 

o 

n 

Leu- 
cocytes. 

4J 

a 

o 

£ 
o 

+3 

o 

"a! 
bb 

3 

1 

M. 

43 

912,000 

37 

3 

7 

0-3 

5-6 

34 

4 

9 

0 

1 

2 

F. 

28 

350,000 

48 

4-6 

2-4 

1-2 

0-9 

32 

3-2 

6 

1 

0 

3 

F. 

21 

412,000 

24 

3 

6 

1 

8 

53-7 

3 

1 

0 

0 

4 

M. 

45 

210,000 

26 

7 

4 

0 

7 

53 

2 

1 

6 

3 

5 

M. 

50 

305,000 

58 

0-5 

1-5 

0-5 

0-5 

36 

2-5 

0-5 

3 

1 

6 

F. 

47 

170,000 

10 

15 

1 

0-5 

5 

65 

3 

0-5 

0 

0 

7 

F. 

39 

470,000 

61 

0 

0 

0-5 

0-5 

37 

0-5 

05 

22 

10 

8 

F. 

32 

500,000 

53 

3-5 

1-5 

1 

4 

24 

0-5 

12-5 

2 

2 

9 

F. 

37 

400,000 

64 

1-5 

1 

1-5 

6 

15 

4 

7 

5 

0 

10 

F. 

23 

8,000 

42 

19 

3 

6 

4 

13 

1 

12 

6 

12 

11 

M. 

33 

116,562 

50 

4 

0 

1 

1-5 

41 

2 

0-5 

7 

7 

12 

F. 

35 

380,000 

66 

4 

8 

1-5 

0-5 

18 

1 

1 

3 

0 

13 

M. 

40 

451,875 

18 

2 

2 

1 

2 

68 

1 

7 

0 

0 

14 

M. 

42 

238,000 

41 

23 

4 

4 

6 

11 

2 

9 

6 

6 

15 

M. 

31 

320,000 

63 

4 

3 

1 

1 

20 

5 

3 

2 

4 

16 

M. 

51 

136,000 

77 

3 

6 

3 

2 

2 

1 

6 

2 

0 

17 

M. 

50 

640,000 

35 

3 

3 

1 

1 

47 

8 

2 

6 

3 

18 

M. 

37 

580,000 

33 

12 

4 

4 

2 

26 

5 

14 

18 

12 

19 

M. 

29 

450,000 

60 

3 

2 

4 

3 

24 

2 

2 

9 

9 

20 

M. 

13 

212,000 

49 

15 

5 

2 

3 

15 

5 

6 

0 

0 

21 

F. 

9 

130.000 

32 

15 

7 

3 

5 

22 

3 

13 

6 

33 

22 

M. 

60 

415,000 

59 

2 

1 

0 

5 

27 

1 

5 

6 

18 

23 

F. 

7 

59,000 

53 

13 

3 

3 

3 

22 

2 

1 

9 

14 

24 

F. 

42 

420,000 

48 

10 

3 

1 

3 

16 

4 

15 

0 

0 

The  table  shows  the  following  variations  :- 
Polymorphs 

Neutrophil  myelocytes  . 
Lymphocytes  (all  sorts) 
Eosinophil  polymorphs  . 
„  myelocytes  . 

Basophils 


10     to  77  per  cent. 

2  „  65 

3  „  13 
0-5  „  8 
0-5  „  8 
0-5  „  15 


1  Folia  Hcematologica,  xii.  Archiv,  1911,  115. 


18     19 

31         7 

.             .             .68     44 

46       58 

2     28 

18       34 

7       7 

1-6      6 

5       2 

3-4      5 

216  LEUCOCYTHiEMIA 

This  marked  variability  was  pointed  out  by  Ehrlieh  long  ago,  and,  like 
him,  we  do  not  find  that  the  alteration  of  percentages  corresponds  to 
any  noticeable  clinical  differences  or  pathological  variations.  Another 
striking  feature  of  myelocythsemia  is  the  capricious  way  in  which  the 
proportions  of  cells  may  vary  from  time  to  time.  The  difference  in  the 
individual  case  may  be  illustrated  by  taking  the  first  one,  in  which,  on 
four  separate  occasions,  the  percentages  were  as  follows : — 

Polymorphs 

Myelocytes 

Lymphocytes 

Basophils 

Eosinophils 

The  blood-plates  may  be  present  in  normal  numbers  or  may  be 
considerably  increased. 

Summary. — In  a  typical  case  the  blood  changes  may  be  said  to 
consist  of — 

1.  A  great  increase  in  all  varieties  of  the  white  cells. 

2.  A  great  invasion  of  myelocytes. 

3.  The  presence  of  numerous  nucleated  red  cells  without  necessarily 
any  ansemia. 

Effect  of  Intercurrent  Disease  on  the  Blood. — The  blood-picture  of 
myelocythsemia  may  be  entirely  altered  and  even  masked  altogether  by 
the  presence  of  an  intercurrent  affection.  Febrile  diseases  are  specially 
likely  to  have  this  effect.  We  have  seen  the  leucocyte  count  fall  from 
225,000  to  8000  during  the  course  of  a  severe  attack  of  influenza.  It 
is  exceptional  for  the  qualitative  changes  to  be  entirely  abolished,  so 
that  the  combination  of  the  splenic  enlargement  and  suspicious  blood- 
picture  might  lead  to  a  diagnosis  of  the  condition,  even  in  the  presence 
of  a  complication.  In  other  cases  the  complication  has  no  effect  on  the 
blood-picture,  but  more  frequently  the  proportion  of  polymorphs  is 
increased,  that  is  to  say,  there  is  an  ordinary  leucocytosis  superadded, 
though  the  total  count  may  not  be  much  altered.  Differences  of  several 
thousand  cells  occur  without  any  special  reason  in  myelocythsemias 
from  day  to  day,  if  the  blood  be  counted  regularly,  so  that  it  is  not  easy 
to  be  sure  whether  a  special  increase  is  necessarily  due  to  a  complication. 

Diagnosis. — The  diagnosis  depends  on  the  blood  examination,  and 
cannot  be  made  without  it.  The  only  possible  difficulty  is  the  occur- 
rence of  a  remission,  or  the  incidence  of  an  intercurrent  affection,  as 
discussed  above.  Ehrlieh  has  laid  stress  on  the  importance  of  a  pro- 
portional increase  of  basophils  in  diagnosis,  and  in  one  case  we  saw  a 


is      "':  i      --_"  'W\  ■'*         '-'O*  >.•.-■"        X 


' '-*-".yA  <■* 


Plate  XIII.-  Myelocyth^mia  (Ehrlich's  Triple  Stain). 


A.  G.,fccil. 


LEUCOCYTILEMIA  217 

leucocytosis  ranging  about  12,000,  with  a  basophil  percentage  varying 
from  12  to  28  per  cent.,  and  an  occasional  neutrophil  myelocyte,  precede, 
by  some  months,  the  onset  of  a  typical  myelocythaemia.  We  have  seen 
other  cases,  however,  come  into  hospital  suffering  from  anaemia  with 
a  high  percentage  of  basophils  and  eosinophils,  and  in  one  case  a  slight 
enlargement  of  the  spleen,  whose  blood,  with  ordinary  treatment,  became 
absolutely  normal,  and  remained  so  for  some  months,  until  the  patients 
dropped  out  of  observation. 

Prognosis. — Prognosis  is  absolutely  unfavourable.  The  acute  cases 
have  died  in  from  fourteen  days  to  eleven  months.  The  duration  of  the 
chronic  cases  is  not  easily  stated,  on  account  of  the  insidious  onset. 
Most  cases  are  likely  to  live  for  at  least  six  months  after  they  first  come 
under  observation.  They  probably  all  die  within  four  or  five  years. 
While  there  is  not  the  same  tendency  to  complete  remission  and 
apparent  return  to  health  as  in  pernicious  anaemia,  the  progress  is  not 
uniformly  downwards.  As  the  result  of  treatment,  and  sometimes 
without  it,  remissions  may  take  place.  In  these  the  spleen  may 
diminish  in  size,  sometimes  considerably,  and  the  leucocyte  count  may 
drop  greatly,  even  perhaps  to  normal,  although  abnormal  cells  can 
generally  be  found.  In  other  cases  the  spleen  and  white  count  may 
remain  unchanged,  but  the  weakness  and  anaemia  from  which  the  patient 
suffered  may  pass  off.  Sooner  or  later,  however,  the  patient  relapses. 
There  is  not  the  same  tendency  to  intercurrent  disease  of  an  infectious 
or  inflammatory  type  as  is  found  in  lymphatic  leukaemia.  This  is 
perhaps  accounted  for  by  the  better  protection  afforded  by  the  large 
number  of  granular  leucocytes  in  the  blood. 

The  fatal  termination  is  generally  the  direct  result  of  anaemia  and 
wasting,  but  a  cerebral  haemorrhage  or  haemorrhage  from  mucous  mem- 
branes, or  attacks  of  delirium  or  coma,  may  immediately  precede  the  end. 

Treatment.  —  Treatment  is  unsatisfactory.  As  long  as  patients 
are  able  to  go  about  and  take  open-air  exercise  they  should  be  encour- 
aged to  do  so.  Should  subjective  symptoms  of  weakness  or  anaemia 
supervene,  patients  should  be  kept  in  bed,  and,  of  course,  symptomatic 
treatment  of  various  kinds  may  have  to  be  resorted  to.  Arsenic  is 
always  worth  a  trial,  given  in  increasing  doses,  as  in  pernicious  anaemia. 
In  the  days  before  X-rays  a  fair  proportion  of  cases  responded  to  this 
treatment,  and  remissions  followed.  Care  should  be  taken  to  avoid 
causing  diarrhoea,  which  is  not  well  borne.  In  some  cases  arsenic 
produces  no  effect,  and  need  not  then  be  continued.     If  the  colour  index 


218  LEUCOCYTILEMIA 

be  low,  iron  may  be  added  with  advantage.  We  have  treated  one  case 
with  atoxyl  and  another  with  soamin  without  bad  or  good  effect  in  either 
case.  Both  cases  had  been  refractory  to  ordinary  arsenic.  Since  the 
introduction  of  salvarsan  we  have  only  felt  ourselves  justified  in 
treating  one  case  with  this  remedy.  The  full  close  was  given  intraven- 
ously. This  was  followed  by  the  usual  rigor  and  sickness,  with  a  little 
diarrhoea,  and  a  swinging  temperature  lasting  for  five  days.  There  was 
no  effect  whatever  on  the  spleen  or  the  blood,  and  though  the  patient, 
after  recovering  from  the  temporary  disturbance,  said  that  she  felt 
stronger,  as  blood  cases  often  say  they  do  after  salvarsan  treatment, 
we  did  not  feel  justified  in  repeating  the  injection.  This  patient  was 
refractory  also  to  ordinary  arsenic  and  to  X-rays,  and  has  since  died. 

Great  things  were  expected  of  X-rays  when  they  were  first  used  in 
the  treatment  of  myelocythEemia.  It  is  beyond  doubt  that  remission 
can  be  brought  about  in  a  larger  proportion  of  cases  than  with  arsenic, 
and  that  the  reduction  in  size  of  the  spleen  and  in  the  number  of  the 
leucocytes  is  often  more  rapid.  In  some  cases  the  spleen  seems  to  melt 
away  almost  from  day  to  day,  while  the  leucocytes  may  drop  by  a 
hundred  thousand,  or  even  more,  in  a  week.  But  in  other  cases  there 
is  a  complete  want  of  response  to  the  treatment,  and  all  grades  of 
response  between  these  extremes  are  met  with.  We  have  not  been  able 
to  determine  the  factors  on  which  this  difference  depends.  Speaking 
generally,  early  cases  in  good  general  health  do  better,  but  this  rule  does 
not  always  hold,  as  we  have  seen  old  cases  do  well  and  presumably 
early  cases  prove  refractory.  But  X-rays  do  not  cure  the  disease,  even  in 
successful  cases.  Recurrences  follow,  and  second  courses  of  irradiation 
are  not  usually  so  successful  as  the  first.  The  interval  of  remission  may 
be  long.  We  treated  a  case  very  successfully  three  years  ago,  and  heard 
of  her  recently  as  being  symptomatically  well. 

When  X-ray  treatment  was  first  started  it  was  applied  over  the 
spleen  only,  but  it  has  been  found  that  better  results  are  obtained  by 
irradiating  the  long  bones  also.  The  body  is  mapped  out  into  areas, 
and  these  are  treated  in  turn.  The  applications  should  be  made  from 
ten  to  twenty  minutes  at  a  time  every  second  or  third  clay.  Great  care 
must  be  taken  to  avoid  burns.  In  a  few  cases  obscure  toxic  symptoms 
have  followed  irradiation,  of  the  same  kind  as  those  seen  when  X-rays 
are  used  in  acute  lymph ocythaemia.  In  cases  which  react  to  treatment 
there  is  first  destruction  of  the  circulating  leucocytes,  especially  those 
of  the  granular  series,  but  as  it  is  continued  the  formation  of  fresh 
leucocytes  is  inhibited.     The  lymphocytes  are  much  less  affected  than 


LEUCOCYTHiEMIA 


219 


the  neutrophils,  basophils,  and  eosinophils,  and  their  resistance  may  be 
so  marked  that  the  blood-picture  may  at  one  stage  resemble  closely  that 
of  a  lymphocythsemia.  During  treatment  the  blood  must  be  fully 
examined  at  least  once  a  week,  for  it  is  possible  to  carry  the  process  so 
far  as  to  exhaust  the  marrow  completely.  This  has  also  been  proved 
experimentally  in  animals.  In  one  of  our  cases  this  was  well  brought 
out.  The  patient  was  responding  well,  was  improving  in  weight,  the 
spleen  was  diminishing,  and  the  whites  falling  rapidly  to  normal.  Our 
resident  physician  had  been  counting  the  whites  regularly,  but  had 
omitted  to  estimate  the  reds  and  haemoglobin  for  some  time.  On  our 
return  from  a  holiday  we  were  struck  by  the  patient's  pallor,  and  on 
examining  the  blood  found  that  it  presented  the  complete  picture  of 
pernicious  anaemia — reds,  3,340,000 ;  haemoglobin,  80  per  cent. ;  colour 
index,  1*2 ;  whites,  3430,  with  a  fair  number  of  megaloblasts,  while  the 
normoblasts  and  myelocytes  had  disappeared.  Stopping  the  X-rays  and 
giving  arsenic  soon  restored  the  reds  to  a  more  normal  condition.  The 
accompanying  table  of  this  case  illustrates  the  course  of  events.  We 
append  also  the  counts  of  a  case  refractory  to  X-rays  which  died  of 
pneumonia  about  six  weeks  after  leaving  hospital.  It  is  unnecessary 
to  quote  more  of  the  successful  cases ;  they  generally  pursue  the  same 
course  as  that  given. 


Reds. 

Haemo- 
globin. 

Colour 
Index. 

Whites. 

10/1/09 

4,S00,00O 

90 

0-9 

600,000 

Before  X-ray  treatment. 

15/1/09 

534,000 

After  one  exposure. 

21/1/09 

483,000 

On  X-rays  thrice  weekly. 

10/2/09 

373,000 

24/2/09 

277,000 

,,          twice  weekly. 

17/3/09 

306,000 

2/4/09 

381,000 

Arsenic  added  to  X-rays. 

9/4/09 

141,000 

13/4/09 

93,000 

20/4/09 

10,900 

27/4/09 

3,340,000 

80 

1-2 

3,400 

X-rays  stopped,  arsenic  stopped. 

4/5/09 

3,700,000 

7S 

1-1 

3,800 

11/5/09 

3,500,000 

73 

1-05 

3,400 

Arsenic  begun  on  12/5/09. 

IS/5/09 

4,150,000 

72 

0-S7 

5,900 

25/5/09 

4,340,000 

73 

0-84 

13,000 

22/6/09 

5,010,000 

SO 

o-so 

9,200 

Discharged  from  hospital,  spleen  just 
below  costal  margin. 

(many 

intermec 

iate  counts  are 

omitted) 

4/9/09 

5,900,000 

85 

0-71 

78,000 

Symptomatically  well ;  went  home  and 
kept  well  for  about  a  year,  but  died 
rather  suddenly  of  pneumonia. 

4.  P.  ( 

refractory  ca 

se) 

16/2/11 

2,450,000 

40 

0-8 

319,400 

X-rays  begun  18/2/11,  and  continued 
twice  weekly. 

25/2/11 

292,000 

4/3/11 

260,000 

11/3/11 

350,000 

20/3/11 

350,000 

Salvarsan  intravenously. 

24/3/11 

337,500 

2/4/11 

345,500 

18/4/11 

3,000,000 

52 

0-86 

400,000 

Spleen  had  not  diminished  in  size  at 
all ;  general  health  rather  improved. 

220  LEUCOCYTELEMIA 

Thorium  X  has  been  tried,  but  is  not  so  useful  as  the  X-rays. 

Benzol  has  recently  come  into  favour  in  the  treatment  of  myelo- 
cythaemia.  The  observation  was  made  by  Sellings  that  workers  in 
benzol  vapour  suffered  from  anaemia  and  leucopenia.  Experiments  on 
rabbits  showed  that  the  drug  had  an  inhibitory  effect  on  the  activity  of 
the  bone-marrow.     On  these  grounds  benzol  has  been  extensively  used. 

Very  variable  results  have  been  noticed.  Distinct  benefit  has  been 
reported  in  several  cases.  In  many  of  these,  however,  the  amelioration 
has  been  transient.  In  some  cases  the  drug  sets  up  gastro-intestinal 
disturbance,  and  cannot  be  tolerated.  In  other  cases  it  has  set  up 
albuminuria.  Again,  it  has  failed  to  bring  about  any  general  improve- 
ment, although  the  leucocyte  count  has  lessened  and  the  size  of  the 
spleen  diminished,  and  yet  again  attacks  of  epistaxis  and  other  haemor- 
rhages have  followed  its  administration. 

It  is  particularly  important  to  note  that  benzol  may  bring  about  a 
leucopenia  just  as  this  may  follow  an  excessive  course  of  X-ray  treat- 
ment. It  is  therefore  imperative  that  its  action  should  be  carefully 
checked  by  frequent  enumerations  of  the  white  cells,  and  the  administra- 
tion should  be  stopped  while  the  leucocyte  count  is  still  well  above  the 
normal,  since  a  fall  may  continue  for  some  time  after  the  drug  has  been 
stopped.  Benzol  is  best  administered  in  the  form  of  capsules  containing 
5  ]\  along  with  5  u\  of  olive  oil.  One  of  these  may  be  given  thrice 
daily,  and  if  no  untoward  symptoms  result  the  dose  may  be  very  gradu- 
ally increased  to  20  n\  thrice  daily,  which  is  about  the  usual  limit  of 
tolerance. 

In  our  own  experience  we  have  met  with  no  very  striking  success 
and  with  no  untoward  result,  except  that  in  some  cases  the  drug  has 
not  been  tolerated  by  the  stomach. 

Two  of  our  cases  developed  a  fairly  severe  febrile  reaction  with  gastro- 
intestinal disturbance  when  the  drug  was  pushed,  and  at  the  height  of 
this  the  leucocyte  count,  which  had  been  240,000  and  184.000,  fell  to 
7000  and  24,000  respectively.  After  the  fever  was  over  the  count 
returned  in  both  cases  to  the  previous  height,  or  rather  above  it.  Such 
a  diminution  in  the  course  of  an  intercurrent  febrile  attack  is  common 
in  myelocythaemia,  and  of  no  significance  from  the  prognostic  point  of 
view. 

There  is  no  doubt,  however,  that  a  considerable  reduction  in  the 
leucocyte  count  is  generally  effected,  and  our  impression  is  that  in  all 
cases  benzol  is  worth  a  trial.  As  a  rule  it  is  not  so  efficacious  as  the 
X-rays,  but  it  can  be  combined  with  X-ray  treatment,  and  may  be 


LEUCOCYTILEMIA  221 

regarded  as  a  fairly  good  substitute  when  the  X-ray  treatment  is 
not  available. 

The  only  other  drug  which  deserves  mention  is  naphthalene  tetra- 
chloride. It  has  occasionally  brought  about  improvement.  The  initial 
dose  is  4  gr.  thrice  daily,  in  cachets,  which  may  be  increased. 

In  view  of  the  effects  of  infections  on  the  blood,  attempts  have  been 
made  to  treat  cases  by  the  use  of  vaccines.  These  have  all  failed. 
Excision  of  the  spleen  has  done  no  good  in  the  few  cases  that  have  sur- 
vived the  operation,  and  as  the  seat  of  the  disease  is  in  the  bone-marrow, 
one  cannot  reasonably  expect  that  splenectomy  would  be  of  service.  All 
operative  procedures  are  extremely  dangerous  and  should  be  avoided. 

3.  Mixed  Foems  of  Leukaemia 

Cases  of  leucocythsemia  are  sometimes  met  with  in  which  the 
blood-picture  is  intermediate  between  that  of  myelocythsemia  and 
lymphocythtemia. 

The  following  case x  may  serve  as  an  example  : — 

Child,  aged  five.  Great  enlargement  of  glands  and  spleen,  retinitis. 
Red  corpuscles,  2,610,000 ;  nucleated  red  cells,  4000  per  c.mm. ;  leuco- 
cytes, 240,000  per  c.mm.;  polymorphs,  16  per  cent.;  lymphocytes,  54 
per  cent. ;  eosinophils,  9  per  cent. ;  mast-cells,  4  per  cent. ;  myelocytes, 
17  per  cent. 

A  few  observations  on  the  course  of  such  cases  have  shown  that 
they  may  arise  in  two  ways  : — 

1.  Cases  of  myelocythsemia  may  become  "  mixed "  cases  by  the 
failure  of  the  marrow  to  elaborate  the  granular  type  of  cell,  or  because 
the  morbid  process  so  accelerates  the  output  of  cells  from  the  marrow 
that  there  is  no  time  for  the  elaboration  of  the  granules.  An  extreme 
instance  of  such  a  case  is  recorded  by  Wilkinson.2  Patient  was  suffer- 
ing from  symptoms  of  myelocythsemia.  The  blood  was  typical  but  for 
the  presence  of  nearly  50  per  cent,  of  lymphocytes.  In  two  days'  time 
the  blood  examination  revealed  a  typical  lymphatic  leukaemia. 

2.  Cases  of  lymphocythsemia  may  become  "  mixed  "  cases  by  the 
lymphocyte  proliferation  acting  as  a  stimulus  to  the  parts  of  the 
marrow  as  yet  unaltered,  with  the  result  that  a  large  number  of 
myelocytes  make  their  appearance,  usually  accompanied  by  an  increase 
in  the  number  of  nucleated  red  rells  in  the  blood. 

1  Fowler,  Interned.  Clinics,  1903. 

2  Wilkinson,  Lancet,  20tli  June  1903. 


222  LEUCOCYTILEMIA 

Another  aspect  is  suggested  by  Herxheimer,1  who  has  published 
a  case  of  "  combined  lymphatic  and  myeloblast  leukaemia,"  in  a  male  aged 
16.  There  were  70,000  leucocytes  per  c.mm.  Of  these  69'8  per  cent, 
were  lymphocytes,  and  25"4  per  cent,  were  myeloblasts. 

In  the  spleen  and  most  of  the  lymph  glands  the  lymphoid  follicles 
were  enlarged.  The  bone-marrow  and  liver  also  showed  a  marked 
lymphocyte  increase  with  smaller  collections  of  myeloblasts.  In  a 
mediastinal  tumour  in  bronchial  glands,  and  in  the  kidneys,  the  cellular 
invasion  consisted  almost  entirely  of  myeloblasts.  The  case  is  regarded 
as  an  acute  development  of  myeloblast  leukaemia  in  a  case  of  longer 
standing  lymphatic  leukaemia.  The  oxydase  reaction  is  relied  on  in 
making  the  distinction,  and  the  case  is  thought  to  afford  evidence  of  the 
dual  origin  of  lymphoid  and  myeloid  tissues. 

It  appears  to  us  that  the  case  might  be  used  as  an  argument  in  the 
contrary  direction.  It  as  readily  suggests  that  the  distinction  between 
lymphocytes  and  myeloblasts  is  a  somewhat  arbitrary  one,  and  that  the 
oxydase  reaction  in  round  nucleated  cells  is  a  matter  of  no  particular 
significance. 

4.  Chloroma 

A  disease  characterised  by  a  leukaemic  condition  of  the  blood  and  by 
the  formation  of  tumours,  sometimes  of  a  greenish  colour,  throughout 
the  body,  but  specially  associated  with  bone.  The  condition  is  very 
rare.  Dunlop,  in  1902,  could  find  records  of  only  twenty-seven  cases. 
The  number  reported  up  to  the  present  time  is  about  sixty.2 

Etiology. — The  disease  is  chiefly  one  affecting  children,  but  it  also 
affects  adolescents,  and  has  occurred  in  a  few  instances  after  thirty.  A 
larger  number  of  cases  have  occurred  in  males  and  females. 

Morbid  Anatomy  and  Pathology. — The  gums  are  often  swollen, 
soft,  and  show  a  pale  greenish  tinge.  Nodules  may  be  seen  in  the 
intestine.  The  lymphoid  masses  may  show  a  greenish  colour.  The 
heart  sometimes  shows  green-coloured  patches  on  its  wall.  The  liver 
is  enlarged  to  a  slight  extent  in  some  cases.  The  kidneys  are  generally 
enlarged  and  may  be  dotted  over  with  greenish  nodules  under  the 
capsule.  The  spleen  is  somewhat  enlarged  but  is  seldom  anything 
like  the  size  which  may  be  reached  in  leukaemia.  The  lymphatic  glands 
are  enlarged  and  pale ;  some  of  them  have  a  green  colour.     The  thymus 

1  Zentralb.f.  Allgem.  Path.  u.  Path.  Anat.,  xxiv.  897. 

2  Hall,  Proc.  Boy.  Soc.  Med.,  ii.  1909,  gives  bibliography. 


LEUCOCYTILEMIA  223 

is  usually  unaffected.  The  bone-marrow  may  be  dark  red  in  colour,  but 
in  many  of  the  bones  the  fatty  marrow  appears  to  be  replaced  by  a 
greenish  pus-like  material. 

Tumours. — The  striking  feature  of  the  disease  is  the  presence  of 
green-coloured  tumours,  chiefly  in  connection  with  the  periosteum  of 
the  bones  throughout  the  body,  but  specially  numerous  in  connection 
with  the  bones  of  the  skull  and  face.  The  tumours  may  be  a  bright 
pea-green  on  section,  but  the  colour  soon  fades.  They  may  cause 
erosion  of  bone. 

On  microscopic  examination  the  infiltrations  of  organs  and  the 
growths  are  found  to  consist  of  round  cells,  having  in  the  majority  of 
cases  the  general  characters  of  lymphocytes.  In  some  cases,  however, 
some  of  the  cells  show  granulations  corresponding  to  the  neutrophil  or 
eosinophil  leucocytes.  In  one  case  we  found  very  large  numbers  of 
basophils.  The  microscopic  appearances  of  the  organs  are  in  other 
respects  similar  to  those  found  in  cases  of  leukaemia. 

The  Pigment. — Little  is  known  regarding  the  nature  of  the  green 
pigment.  It  fades  fairly  rapidly  on  exposure  to  air,  and  has  altogether 
disappeared  from  microscopic  sections  by  the  time  they  have  been  pre- 
pared. The  pigment  is  affected  by  differences  in  its  amount  of  oxygen. 
Dunlop  found  that  the  colour  could  be  restored  by  the  application  of 
reducing  agents.  Hall,  Hebb,  and  Bernstein 1  found  that  it  was  bleached 
by  peroxide  of  hydrogen.  On  the  other  hand,  Trevithick  2  found  that 
the  green  colour  was  restored  by  the  application  of  peroxide  of  hydro- 
gen, an  observation  which  we  could  confirm  in  one  case  and  not  in 
another.  The  pigment  is  insoluble  in  alcohol,  chloroform,  and  ether. 
It  is  at  least  partially  soluble  in  3  per  cent,  acetic  acid,  boiling  water, 
and  possibly  boiling  alcohol  and  ammonia.  Pope  and  Reynolds  regard 
it  as  a  fatty  acid  combined  with  iron. 

The  pathogenesis  of  the  disease  is  unknown.  This  disease  affords 
strong  evidence  in  favour  of  the  view  that  the  leukaemias  are  of  the 
nature  of  sarcomata.  In  chloroma  there  is  a  useless  hyperplasia  of  the 
cells  of  bone-marrow.  These  cells  pass  into  the  blood-stream  and  invade 
all  the  tissues  and  organs  of  the  body.  They  may  give  rise  to  metastatic 
growths,  and  for  some  unknown  reason  the  metastases  seem  to  have  a 
selective,  though  by  no  means  exclusive,  affinity  for  periosteum. 

Symptoms. — As  in  ordinary  leukaemia,  symptoms  are  not  much  in 

1  Proc.  Roy.  Soc.  of  Med.,  1909. 

2  Lancet,  22nd  August  1903. 


224  LEUCOCYTILEMIA 

evidence  until  the  disease  has  made  considerable  progress.  Patches  of 
ecchymosis,  soreness  of  the  gums,  deafness,  hoarseness,  or  the  presence  of 
actual  tumours  or  proptosis  may  call  attention  to  the  condition.  Much 
more  rarely  the  patient  complains  of  general  weakness  or  ill-health. 

As  the  disease  develops  the  tumours  about  the  face  and  head 
enlarge,  and  become  very  striking.  There  may  be  proptosis  to  such 
an  extent  that  the  patient  cannot  close  the  eyes.  The  conjunctivae 
may  become  infiltrated  with  either  a  flesh-coloured  or  greenish-yellow 
growth,  leading  to  blindness.  The  intracranial  growths  may  cause 
vascular  engorgement,  thrombosis  of  sinuses,  or  compression  of  cranial 
nerves  or  even  of  the  brain.  The  nervous  tissue  is  not  actually 
invaded.  Deafness  and  other  aural  symptoms  are  common  from  growths 
in  the  middle  or  internal  ear.  Nodular  eruptions  may  appear  on  the 
skin  all  over  the  body.  The  usual  lesion  is  in  the  form  of  flat-topped 
nodules,  varying  in  size  from  a  pin's  head  to  a  shilling.  They  are 
generally  painless  and  freely  movable.  There  may  be  extravasations 
of  blood  in  the  eye,  and  retinitis  and  optic  neuritis  may  occur.  There 
is  a  marked  tendency  to  haemorrhages,  especially  from  the  gums  and 
mucous  membranes.  Petechial  and  other  haemorrhages  into  the  skin 
occur.     In  one  case  a  profuse  haemorrhage  took  place  from  the  orbit. 

The  Blood  Changes. — The  usual  picture  is  that  of  a  typical  lymphatic 
leukaemia.     This  is,  however,  by  no  means  constant. 

In  Bramwell's 1  case  the  total  number  of  white  cells  was  8000  per 
c.mm.,  with  95  per  cent,  of  lymphocytes.  In  Pribram's2  case  there 
were  10,000  white  cells  at  first,  and  later  their  number  fell  to  800. 
Again,  cases  occur  in  which  there  is  a  large  proportion  of  myelocytes. 
As  many  as  32  per  cent,  have  been  noted  by  more  than  one  observer. 
Eosinophils  and  basophils  may  be  numerous.  There  is  practically 
always  some  degree  of  anaemia,  and  as  the  case  advances  it  becomes 
very  severe. 

Diagnosis. — The  diagnosis  depends  upon  the  presence  of  the  tumours, 
or  of  some  feature  such  as  proptosis  indicating  their  existence,  along 
with  the  characteristic  blood  changes. 

Prognosis. — Cases  of  chloroma  are  quite  hopeless.  The  fatal  termina- 
tion may  be  brought  about  in  the  same  ways  as  in  leukaemia,  but  with 
a  tendency  to  more  rapid  emaciation  and  with  a  greater  likelihood  of 
some  pressure  symptom  occurring. 

1  Trans.  Edin.  Med.  Chirurg.  Soc,  xxi.  1902. 

2  Munch,  med.  Wochenschr.,  1909,  No.  40,  2086. 


LEUCOCYTHyEMIA  225 

Treatment. — Treatment  is  on  the  same  general  lines  as  that  of  acute 
lymphatic  leukaemia. 

Leuc  anaemia 

This  term  was  introduced  by  Leube  to  denote  a  condition  of  the 
blood  presenting  the  chief  features  of  myelocythaemia  and  of  pernicious 
anaemia. 

The  red  cells  may  fall  to  below  one  million.  The  colour  index 
becomes  high,  and  there  are  numerous  megaloblasts  and  normoblasts. 
The  white  cells  show  a  large  number  of  myelocytes  and  lymphocytes, 
but  eosinophils  and  basophils  are  scanty.  The  qualitative  changes  may 
be  seen  without  any  actual  increase  in  the  number  of  leucocytes.  In 
one  or  two  cases  there  has  been  an  actual  leucopenia,  and  if  a  case 
were  seen  at  that  time  there  might  be  ground  for  a  diagnosis  of 
pernicious  anaemia. 

In  the  cases  which  have  been  examined  after  death  the  general 
appearances  have  been  those  of  myelocythaemia.  The  liver  in  a  few 
cases  has  shown  marked  siderosis,  which  is  precisely  what  we  find  in 
a  few  cases  of  myelocythaemia.  The  marrow  shows  a  myelocytic  re- 
action, but  lymphocytes  are  abundant.  There  is  a  considerable  amount 
of  megaloblastic  change.  These  appearances  might  lead  one  to  suppose 
that  leucanaemia  was  a  mixture  of  the  two  conditions.  This  is  so  far 
true.  But  it  may  be  pointed  out  that  in  nearly  all  cases  of  pernicious 
anaemia  there  is  a  myelocytic  reaction  on  the  part  of  the  red  marrow, 
and  that  in  all  cases  of  myelocythaemia  the  marrow  shows  a  varying 
degree  of  megaloblastic  change. 

Leucanaemia  is  simply  a  phase  in  the  course  of  cases  of  leukaemia, 
and  illustrates  what  we  have  already  said  regarding  the  great  variability 
of  the  blood-picture  in  that  disease  within  certain  definite  boundaries. 
It  further  emphasises  the  necessity  of  repeated  examinations  of  the 
blood  in  any  atypical  or  ill-defined  case  before  a  conclusion  is  reached. 
We  have  seen  the  blood-picture  of  "  leucanaemia  "  develop  in  the  course 
of  cases  of  myelocythaemia  as  the  result  of  treatment  by  X-rays  or 
without  apparent  cause,  and  at  a  later  stage  the  typical  blood-picture 
of  myelocythaemia  has  returned. 

We  think  the  term  could  with  advantage  be  dropped.      It  may 

indicate  a  certain  symptom-complex  which  might  be  understood  by  the 

expert,  but  he  is  likely  to  maintain  a  healthy  scepticism  until  he  has 

seen  the  figures.      To  the  practitioner  who  has  not  specially  studied  the 

literature  of  haematology  the  term  is  likely  to  be  meaningless. 

15 


CHAPTEE  XXII 

LYMPHADENOMA— HODGKIN'S   DISEASE 

Definition. — A   disease   characterised    by  progressive  enlargement    of 
lymphatic  glands,  hyperplasia  of  lymphoid  organs,  and  aneemia. 

Etiology. — The  disease  is  most  common  between  the  ages  of 
thirty  and  forty.  It  is  fairly  common  below  twenty,  less  common 
between  forty  and  fifty,  and  there  is  again  an  increase  after  fifty.  The 
disease  is  three  times  as  common  in  males  as  in  females.  Some  cases 
have  suggested  an  infective  origin.  Ptolleston  refers  to  a  case  begin- 
ning in  the  axilla  after  a  poisoned  finger.  It  has  followed  disease  of 
the  ear,  chronic  nasal  or  pharyngeal  catarrh,  local  injuries,  and  such 
operations  as  the  removals  of  tonsils. 

Pathology. — There  is  extensive  enlargement  of  glands  either  through- 
out the  body  or  in  large  groups.  The  glands  are  mostly  discrete,  but 
a  few  of  them  may  be  confluent.  The  spleen  is  enlarged  to  a  variable 
extent  in  over  75  per  cent,  of  cases,  and  in  one  or  two  cases  the  sug- 
gestion has  been  made  that  the  splenic  enlargement  was  the  primary 
lesion.  The  liver  may  be  slightly  enlarged.  There  are  sometimes 
collections  of  cells  which  give  rise  to  "  suet-like  "  nodules,  visible  to  the 
naked  eye,  most  often  in  the  spleen,  but  sometimes  in  liver  and 
kidney  also. 

The  histological  change  in  the  lymphatic  glands  is  a  diminished 
activity  of  the  germ  centres,  so  that  the  reticulum  is  not  obscured  and 
the  sections  have  a  homogeneous  appearance.  There  is  a  great  promin- 
ence and  proliferation  of  the  endothelial  cells  and  cells  of  the  reticulum. 
Some  of  these  cells  attain  a  large  size  and  contain  four  or  more  nuclei. 
These  are  "  lymphadenoma  cells,"  and  differ  from  the  giant  cells  of 
tuberculosis  in  their  smaller  size,  and  in  the  structure  of  the  nuclei. 
Eosinophil  cells  are  nearly  always  present,  sometimes  in  small  numbers, 
sometimes  very  abundant.  They  are  often  of  "  myelocyte "  type,  and 
are  probably  produced  locally  and  not  immigrants  from  the  bone- 
marrow.     In  the  early  stages  there  may  be  little  or  no  formation  of  the 


LYMPHADENOMA— HODGKIN'S   DISEASE  227 

giant  cells,  and  in  the  later  stages  there  is  always  a  great  increase  of 
fibrous  tissue.  There  is  no  essential  difference  between  the  "  hard  " 
and  "  soft  "  type  of  enlarged  gland.  The  "  soft  "  type  is  the  early  stage, 
the  "  hard  "  the  later  one.  In  the  same  group  of  glands  the  two  stages 
may  be  found. 

The  spleen  is  fibrous.  The  Malpighian  corpuscles  are  present  but 
are  small.  Cells  of  the  reticulum  and  endothelial  cells  proliferate,  and 
giant  cells  of  the  lymphadenomatous  type  are  generally  abundant. 
Eosinophils  are  in  varying  amount.  The  nodules  in  the  liver  and  other 
organs  consist  of  lymphocytes.  They  are  surrounded  by  a  reticulum, 
and  according  to  Adami  they  develop  from  the  lymphocytes  normally 
present  in  the  fibrous  tissue  of  the  perivascular  sheaths. 

In  most  cases  there  is  a  moderate  increase  of  myelocytic  activity  in 
the  bone-marrow,  and  in  many  cases  a  great  increase  of  eosinophils  has 
been  noticed. 

The  widespread  distribution  of  the  lesions  is  to  be  explained  by  their 
origin  in  lymphoid  tissue  and  not  by  a  process  of  metastasis.  The 
exciting  cause,  whatever  that  may  be,  seems  to  affect  lymphoid  tissue 
over  a  large  area.  The  general  picture  is  much  more  suggestive  of  a 
general  irritation  than  of  malignant  disease. 

The  actual  cause  of  the  disease  is  unknown.  Much  bacterial  re- 
search has  been  made  with  the  object  of  throwing  light  on  the  subject. 
White  and  Proscher  described  a  spirochsete  as  occurring  in  the  glands. 
This  has  not  been  confirmed.  Frankel  and  Much  have  found  a  bacillus 
morphologically  identical  with  the  tubercle  bacillus  but  not  acid  fast. 
Diphtheroid  organisms  apparently  similar  have  been  described  by  Negri 
and  Mieremet.1  Bunting  and  Yates 2  have  also  found  bacteria  which  they 
think  identical  with  those  described  by  Negri  and  Mieremet.  They  have 
named  the  organism  Gorynebacterium  granulomatis  maligni.  Billings 
and  Bosenow3  have  isolated  an  organism  in  twelve  cases — nine  in  pure 
culture — and  have  had  some  success  with  vaccines  prepared  from 
cultures.  Attempts  to  inoculate  the  disease  into  animals  have  all  failed 
or  at  least  been  inconclusive. 

Symptoms. — The  first  indication  of  the  disease  is  glandular  enlarge- 
ment. The  cervical  glands  are  more  frequently  affected  than  others ; 
after  these  in  order  of  frequency  are  the  axillary,  inguinal,  retroperitoneal, 

1  Gentralb.  f.  Bad.  1913. 

2  Arch,  of  Int.  Med.,  xii.  1913. 

3Journ.  Amer.  Med.  Assoc,  November  1913. 


228  LYMPHADENOMA— HODGKIN'S   DISEASE 

mediastinal,  bronchial,  and  mesenteric.  A  division  can  often  be  made 
into  cases  in  which  the  glandular  enlargement  is  mainly  superficial, 
cases  in  which  the  symptoms  are  mainly  due  to  intrathoracic 
enlargements,  and  cases  in  which  the  symptoms  are  mainly  abdominal. 

Superficial  Gland  Form. — The  primary  glandular  enlargement  may 
be  in  existence  for  weeks,  months,  or  even  a  couple  of  years  before  other 
symptoms  become  marked.  The  size  of  the  glands  may  show  great 
fluctuations.  During  febrile  attacks  new  groups  of  enlarged  glands  may 
become  noticeable,  and  glands  previously  involved  may  become  larger 
and  softer.  In  afebrile  intervals  the  glands  often  become  smaller  and 
firmer.  The  glands  are  generally  firm  and  elastic,  and  are  usually 
discrete  and  freely  movable.  In  a  few  cases  they  may  become  confluent, 
and  in  some  instances  they  are  quite  soft  to  the  touch.  Soft  and  hard 
glands  may  exist  in  the  same  neck,  and  soft  glands  may  become  hard 
and  hard  glands  may  become  soft. 

The  Thoracic  Form. — The  enlargement  of  glands  in  the  thorax  may 
give  rise  to  symptoms  similar  to  those  of  mediastinal  tumour.  As  a 
rule  the  occurrence  of  the  intrathoracic  growths  is  a  late  development, 
but  in  rare  instances  it  constitutes  the  earliest  and  main  feature  of  the 
disease.  There  may  be  pressure  on  the  oesophagus  leading  to  dysphagia. 
Pressure  on  veins  may  lead  to  great  engorgement  of  superficial  veins  of 
the  neck,  face,  and  arms,  with  cyanosis,  and  sometimes  even  exophthalmos 
and  oedema  of  the  conjunctiv£e.  There  may  be  pressure  on  the  trachea 
or  bronchi  giving  rise  to  great  dyspnoea.  Sometimes  the  lymph- 
adenomatous  growths  set  up  bronchitis  or  pleurisy,  and  in  the  latter 
the  effusion  has  been  chylous  in  a  few  instances.  The  dyspnoea  and 
fever  may  suggest  pneumonia.  Pressure  on  the  recurrent  laryngeal 
nerve  may  cause  paralysis  of  a  vocal  cord. 

The  Abdominal  Form. — The  abdominal  manifestations  of  lymph- 
adenoma  usually  follow  some  time  after  the  superficial  glands  have  been 
enlarged.  There  are  instances,  however,  in  which  the  retroperitoneal 
glands  have  been  primarily  attacked.  In  one  of  our  cases  the  first 
gland  to  be  attacked  was  apparently  the  most  superficial  of  the  glands, 
lying  along  the  left  external  iliac  artery.  The  presence  of  these  glands 
may  suggest  a  diagnosis  of  tuberculous  peritonitis.  Stuart  M'Donald 
refers  to  a  case  in  which  pain  and  resistance  in  the  upper  part  of  the 
abdomen  led  to  an  operation  for  a  supposed  leaking  gastric  ulcer. 
Pressure  by  the  enlarged  glands  may  lead  to  intestinal  obstruction  or 
dilatation  of  the  colon,  and  symptoms  may  simulate  appendicitis.  Pro- 
fuse diarrhoea  is  a  rare  symptom.     Pressure  on  the  bile  ducts  may  set 


LYMPHADENOMA— HODGKIN'S   DISEASE  229 

up  jaundice,  which  may  vary  with  variations  in  the  size  of  the  glands 
and  often  corresponds  to  febrile  attacks.  Jaundice  is  a  fairly  common 
symptom  towards  the  end.  A  degree  of  biliary  cirrhosis  may  be  set  up. 
Either  from  pressure  on  the  portal  fissure  or  from  the  growths  elsewhere 
setting  up  irritation  ascites  may  occur.  It  is  generally  serous,  but  is 
sometimes  chylous,  and  in  a  few  instances  a  pseudo-chylous  ascites  has 
been  found.  Pressure  on  the  inferior  vena  cava  may  cause  albuminuria 
and  oedema  of  the  lower  limbs,  and  pressure  on  the  ureters  may  interfere 
with  the  excretion  of  urine.  Sciatica  and  other  pains  may  be  set  up  by 
pressure  on  the  nerves  of  the  lumbar  and  sacral  plexuses. 

The  Liver. — The  liver  is  by  no  means  always  enlarged,  but  in  some 
cases  its  size  may  be  considerably  increased.  The  enlargement  may 
come  on  suddenly  in  the  course  of  a  febrile  attack.  Enlargement  of  the 
liver  without  enlargement  of  superficial  glands  may  give  rise  to  very 
considerable  difficulties  in  diagnosis.  Abscess  of  the  liver  may  be 
simulated  in  febrile  cases,  and  congenital  syphilis  may  be  suggested  in 
a  young  subject. 

The  Spleen. — The  spleen  is  somewhat  enlarged  in  most  cases.  It  is 
nearly  always  enlarged  in  abdominal  cases,  and  in  a  few  instances  splenic 
enlargement  may  be  the  outstanding  feature  of  the  disease.  Symmers 
has  published  a  case  in  which  there  was  primary  lymphadenoma  of 
the  spleen.  In  this  case  and  in  others  in  which  the  spleen  and 
retroperitoneal  glands  are  alone  involved  the  resemblance  to  splenic 
anaemia  may  be  very  close.  Parkes  Weber  records  a  remarkable  case 
in  which  there  was  at  one  time  enlargement  of  superficial  glands.  At 
a  later  period  the  glandular  enlargement  had  disappeared,  and  there  was 
enlargement  of  the  spleen,  ascites,  and  anaemia  with  leucopenia.  Post- 
mortem examination  revealed  enlargement  of  thoracic  and  abdominal 
lymph  glands.  Enlarged  glands  in  the  hilus  of  the  liver  probably 
accounted  for  the  ascites.  The  diagnosis  was  confirmed  with  the  micro- 
scope.    In  malarial  districts  the  splenic  cases  may  suggest  that  disease. 

Temperature. — In  the  early  stages,  except  in  very  acute  cases,  there 
is  usually  no  rise  of  temperature,  but  sooner  or  later  fever  supervenes. 
Three  distinct  types  were  distinguished  by  Gowers — (1)  A  persistent 
mild  fever  with  a  diurnal  variation  of  not  more  than  a  degree  and  a  half. 
(2)  A  high  irregular  temperature  with  morning  remissions  to  100°  F. 
This  type  is  especially  liable  to  occur  in  the  later  stages,  and  as  it  may 
then  be  accompanied  by  rigors  and  perspirations,  a  septic  condition  may 
be  closely  simulated.  (3)  An  intermittent  fever  lasting  for  about  ten 
days  or  a  fortnight,  succeeded  by  an  apyretic  interval  of  about  the 


230  LYMPHADENOMA— HODGKIN'S   DISEASE 

same  duration.  The  temperature,  as  a  rule,  rises  about  a  degree 
each  evening  and  falls  about  half  a  degree  each  morning,  so  that 
at  the  end  of  a  week  it  has  reached  103°  E.  The  following  week 
the  morning  fall  exceeds  the  evening  rise,  so  that  the  temperature  is 
again  normal  at  the  end  of  the  second  week.  This  relapsing  fever 
may  continue  for  over  a  year,  and  persist  till  death  takes  place,  or 
merge  into  the  second  form.  During  the  pyrexial  periods  the  symp- 
toms are  aggravated.  The  glands  may  enlarge  and  the  skin  over  them 
may  redden.  The  spleen  becomes  bigger.  The  patient  emaciates  and 
suffers  from  dyspepsia  and  the  usual  symptoms  of  fever.  In  some  of 
these  cases  without  much  enlargement  of  superficial  glands  a  diagnosis 
of  typhoid  fever  might  be  thought  of.  In  some  cases  there  are  long 
remissions  without  fever,  sometimes  preceded  and  always  followed  by 
fever  of  one  of  the  above  types.  In  our  experience  the  third  type  is 
commonest  (in  true  lymphadenoma)  during  the  course  of  the  disease, 
merging  towards  the  end  of  the  case  into  the  second  type. 

Cutaneous  Symptoms. — Intense  itching  of  the  skin  is  an  uncommon 
and  capricious  but  sometimes  a  very  distressing  symptom.  Loss  of  hair 
and  changes  in  its  texture  have  been  noticed.  Bronzing  of  the  skin 
sometimes  occurs.  Bramwell  records  two  cases  in  which  bronzing  of 
the  skin  and  leucodermia  preceded  any  noticeable  enlargement  of  glands. 
It  is  possible  that  such  cases  are  to  be  accounted  for  by  interference 
with  the  functions  of  the  suprarenals.  Lymphadenomatous  nodules 
sometimes  occur  in  the  skin,  and  are  subject  to  the  regressive  changes 
which  are  seen  in  the  glands.  Erythema,  dermatitis,  and  bullous  erup- 
tions have  occurred.  Purpura  has  been  described.  Most  of  the  cases 
were  probably  leukaemia,  but  in  the  anaemic  stage  purpura  sometimes 
does  occur  in  true  lymphadenoma. 

Nervous  Symptoms.  —  In  some  cases  symptoms  suggestive  of  such 
lesions  as  tabes  have  occurred.  Tremor,  delirium,  stupor  or  coma  may 
be  seen  as  terminal  symptoms. 

The  Blood  Changes. — In  the  early  stage  the  blood  may  show  no 
change.  As  the  disease  develops  there  is  always  anaemia,  which  may 
become  severe.  The  red  cells  may  fall  to  2,000,000  or  even  fewer,  and 
normoblasts  may  be  present.  The  colour  index  is  lowered.  The  number 
of  white  cells  may  show  no  change.  The  idea  that  there  is  an  increase 
of  lymphocytes  in  lymphadenoma  dies  hard.  In  a  quite  recent  paper  it 
is  seriously  suggested  that  the  number  of  leucocytes  is  from  10,000  to. 
12,000,  with  51  per  cent,  of  lymphocytes.     This  is  not  our  experience. 


LYMPHADENOMA— HODGKIN'S   DISEASE  231 


Fig.  25. — Case  of  Hodgkin's  Disease. 


Fig.  26. — Same  Case,  three  months  later. 


232  LYMPHADENOMA— HODGKIN'S   DISEASE 

In  some  cases  there  is  little  alteration  in  the  leucocyte  picture  from 
first  to  last.  In  some  cases  the  polymorphs  are  diminished  as  an 
expression  of  the  ill-health  of  the  patient.  Such  cases  of  course 
show  a  "  relative  lymphocytosis."  Much  more  commonly  there  is 
a  slight  leucocyte  increase  clue  to  an  increase  in  the  number  of  poly- 
morphs. This  is  more  marked  in  the  febrile  attacks,  the  polymorph 
percentage  and  the  leucocyte  count  often  increasing  in  proportion  to 
the  temperature. 

Considerable  fluctuations  in  the  leucocyte  count  may  occur.  In  the 
case  illustrated  in  Figs.  25  and  26  the  count  (in  thousands  per  c.mm.) 
on  9th  May  was  40,  but  by  the  11th  it  had  fallen  to  17.  This  was 
followed  by  a  steady  rise  to  61  on  1st  June,  and  a  somewhat  steady 
sequence  of  rise  and  fall,  each  phase  extending  over  ten  days,  then 
ensued.  The  larger  counts  occasionally,  but  by  no  means  constantly, 
corresponded  to  febrile  attacks.  Several  times  a  diurnal  variation  of 
10,000  leucocytes  was  found.  The  evening  count  was  usually  lower 
than  the  morning  one. 

Occasionally  there  is  a  marked  eosinophilia.  In  one  of  our  cases 
there  was  a  slight  increase  of  basophils  as  well  as  of  eosinophils.  The 
white  cells  numbered  12,000 ;  polymorphs,  78  per  cent. ;  lymphocytes, 
15  per  cent. ;  eosinophils,  4  per  cent. ;  and  basophils,  3  per  cent.  In 
another  case  there  was  a  high  polymorph  leucocytosis  to  begin  with, 
and  later  this  was  associated  with  a  high  degree  of  eosinophilia,  which 
persisted  till  the  patient  died. 

The  glycogen  reaction  is  sometimes  mildly  positive  at  the  height  of 
febrile  attacks  in  lymph  adenoma,  and  is  fairly  constant  in  the  last  stage, 
probably  as  the  result  of  terminal  infection. 

Course  and  Prognosis. — Some  cases  appear  to  run  an  acute  course. 
"We  have  seen  cases  which  have  died  within  three  or  four  months  of 
coming  under  observation,  but  there  is  always  some  doubt  as  to  the 
previous  history  of  the  illness.  Some  apparently  acute  cases  are  really 
the  acute  termination  of  a  chronic  condition.  The  usual  course  of  the 
disease  is  a  chronic  one.  The  duration  varies  considerably.  The  febrile 
cases  are  not  likely  to  live  more  than  a  year,  and  death  in  any  case  is 
likely  to  take  place  within  three  years.  Long  remissions  of  symptoms, 
however,  sometimes  occur,  and  pressure  symptoms  may  disappear. 

We  can  recall  a  case  in  which  there  was  pressure  on  the  right  lung 
causing  collapse,  and  pressure  on  the  superior  vena  cava.  These  symp- 
toms entirely  disappeared,  and  at  a  later  date  enlarged  glands  made 


LYMPHADENOMA— HODGKIN'S   DISEASE  233 

their  appearance  above  the  left  clavicle.  One  of  these  was  excised 
and  the  diagnosis  was  confirmed  by  the  microscope.  At  a  still  later 
stage  these  glands  in  their  turn  disappeared  also. 

In  another  case  there  was  obstruction  of  veins  and  phlebitis  in  the 
left  leg,  but  these  symptoms  all  cleared  up. 

Death  may  be  due  to  an  intercurrent  affection  such  as  tuberculosis  or 
pneumonia.  Pressure  on  the  trachea  or  vital  organs  is  said  to  be  the 
most  usual  termination,  but  in  our  experience  death  from  asthenia  or 
intercurrent  affections  is  more  common.  In  the  absence  of  these 
contingencies  the  patient  may  become  very  aneemic  and  cachectic,  and 
finally  die  from  asthenia. 

Diagnosis. — It  appears  that  out  of  a  mass  of  conflicting  evidence 
there  now  stands  out  with  some  degree  of  clearness  a  definite  condition 
with  pathological  features  as  described  by  Greenfield,  Andrewes,  Pteed 
and  Longcope,  and  it  is  the  condition  which  we  have  kept  in  view  in 
the  foregoing  description.  In  dealing  with  symptoms  we  have  mentioned 
the  conditions  which  may  be  confounded  with  local  manifestation  of 
lymphadenoma.  "We  have  now  to  discuss  the  diagnosis  in  a  more 
general  way.  The  first  essential  in  the  diagnosis  is  to  make  a  satis- 
factory examination  of  the  blood.  The  positive  evidence  in  favour  of 
lymphadenoma  may  not  amount  to  much,  but  a  whole  host  of  other 
•conditions  may  be  excluded. 

The  conditions  which  have  to  be  distinguished  are  as  follows : — 
1.  Ttcber  miosis. — The  distinction  between  this  and  lymphadenoma 
may  be  extremely  difficult.  Sternberg  regards  lymphadenoma  as  a 
special  form  of  tuberculosis,  and  we  must  confess  that  of  all  the  cases 
we  have  seen  diagnosed  clinically  as  lymphadenoma  and  afterwards 
come  to  the  post-mortem  room,  a  larger  number  have  been  tuberculosis 
or  lymphadenoma  complicated  with  tuberculosis  than  pure  lymph- 
adenoma. A  large  number  of  cases  diagnosed  clinically  as  lymphadenoma 
are  found  to  be  tuberculosis  when  injections  of  the  glands  are  made 
into  guinea-pigs.  On  the  other  hand,  the  number  of  negative  inocu- 
lations is  too  large  to  be  ignored.  A  von  Pirquet  or  Koch  test,  if 
negative,  would  be  of  some  value  in  excluding  tubercle.  A  positive 
reaction  would  not  necessarily  exclude  lymphadenoma,  since  the  two 
conditions  are  so  often  combined.  An  actual  lymphocytosis  is  in  our 
opinion  much  more  likely  to  be  indicative  of  tuberculosis  than  of 
lymphadenoma.  Excision  of  a  gland  makes  the  diagnosis  clear  if  the 
gland   in  question  happens  to  be   typical    of   either  condition,    or   if 


234  LYMPHADENOMA— HODGKIN'S   DISEASE 

tubercle  bacili  can  be  demonstrated,  but  we  have  often  found  it  neces- 
sary to  examine  many  specimens  before  an  opinion  could  be  given  even 
on  post-mortem  specimens.  Our  own  practice  is  to  excise  a  gland 
in  every  doubtful  case,  where  this  can  be  done  with  safety,  to  examine 
one  portion  histologically  and  to  make  inoculations  with  another.  We 
have  seen  numerous  cases  in  which  a  diagnosis  would  have  been  impos- 
sible without  the  use  of  this  method.  The  temperature  chart  will  in 
time  help  to  distinguish  the  conditions.  Tuberculosis  does  not  show 
the  severer  forms  of  fever  found  in  lymphadenoma  unless  there  is  septic 
infection.  If  there  be  septic  infection  the  blood  will  show  increase 
of  fibrin  and  absence  of  eosinophilia,  neither  of  which  is  found  in 
lymphadenoma. 

2.  Malignant  Disease,  —  Difficulty  in  differential  diagnosis  often 
arises,  especially  in  the  case  of  primary  malignant  disease  in  the 
mediastinum  or  retroperitoneal  region,  and  also  in  cases  of  metastatic 
affection  of  glands  when  a  primary  tumour  is  not  obvious.  There  may 
be  just  as  much  difficulty  in  distinguishing  between  lymphosarcoma 
and  lymphadenoma  running  an  acute  course  as  there  is  in  distinguishing 
between  tuberculosis  and  the  commoner  variety  of  lymphadenoma.  In 
some  of  the  cases  of  acute  lymphadenoma  the  leucocytosis  and  eosino- 
philia is  greater  than  that  usually  seen  in  malignant  disease.  In  some 
cases  of  generalised  lymphosarcoma  there  may  be  an  increase  of  white 
cells  with  a  high  percentage  of  lymphocytes.  The  temperature  changes 
of  lymphadenoma  will  probably  be  a  serviceable  diagnostic  symptom 
in  most  cases  of  doubt.  In  lymphosarcoma  the  glands  usually  become 
confluent  and  form  large  masses,  and  there  may  be  invasion  of  sur- 
rounding tissues,  while  in  lymphadenoma  the  glands  remain  separate. 
The  occurrence  of  remissions  would  favour  the  diagnosis  of  lymph- 
adenoma rather  than  malignant  disease.  Whenever  possible  a  gland 
should  be  excised  for  microscopic  investigation. 

3.  Leucocythcemia. — The  diagnosis  can  be  made  quite  readily  from 
the  blood  examination. 

4.  Aleulzwmic  Leukamiia. — We  confess  to  a  difficulty  in  understanding 
what  this  monstrosity  of  pathological  nomenclature  may  mean,  in  spite 
of  the  prolixity  of  writers  on  the  subject.  If  we  take  it  to  be  early 
leukaemia,  before  there  is  any  glandular  enlargement,  then  there  is  no 
reasonable  likelihood  of  it  being  confused  with  lymphadenoma.  If 
leukaemia  is  associated  with  glandular  enlargement  we  should  find 
the  usual  blood  changes,  since  the  glandular  enlargement  is  secondary 
to  the  blood  condition. 


LYMPHADENOMA— HODGKIN'S   DISEASE  235 

5.  Local  glandular  enlargement  due  to  inflammatory  processes, 
syphilis,  filariasis,  etc.,  may  give  rise  to  difficulty.  In  inflammatory 
conditions  there  is  usually  an  obvious  cause.  Febrile  syphilis  may 
closely  resemble  lymphadenoma.  The  diagnosis  will  be  determined  by 
the  history,  the  Wassermann  reaction  or  the  luetin  reaction  of  ISToguchi, 
the  incidence  of  other  symptoms  of  syphilis,  and  the  effect  of  treatment. 
Filariasis  will  be  distinguished  by  the  examination  of  the  blood  and  of 
the  gland  juices. 

Treatment. — The  patient  should  lead  an  open-air  life  as  long  as  his 
strength  permits.  He  should  have  good  food  up  to  the  limits  of  his 
digestion.  Arsenic  seems  to  benefit  symptoms.  Very  striking  benefit 
has  followed  the  exhibition  of  some  of  the  organic  preparations  of 
arsenic,  and  we  have  seen  cases  in  which  symptoms  disappeared  in  the 
course  of  a  few  days  after  an  injection  of  salvarsan.  No  permanent  cure 
has  ever  been  recorded.  Surgical  interference  seems  to  be  useless,  and 
in  some  cases  one  gets  the  impression  that .  the  growth  of  glands  has 
been  more  rapid  about  the  seat  of  operation  than  before. 

In  1911  we  published  a  case  which  is  of  great  interest  because  of 
the  striking  temporary  improvement  produced  by  the  intravenous  injec- 
tion of  salvarsan  (0*6  grm.).  The  patient  had  for  some  months  suffered 
from  the  undulatory  relapsing  type  of  fever — ten  days'  fever,  culminat- 
ing on  the  fifth  or  sixth  day  at  103°,  followed  by  ten  days  of  normal 
temperature,  and  then  again  by  fever,  and  so  on.  At  the  end  of  one  of 
the  febrile  attacks  the  temperature  continued  high.  An  injection  of 
salvarsan  into  the  buttock  caused. very  slight  improvement  for  a  day  or 
two,  but  the  fever  went  on,  the  patient  emaciated,  and  was  obviously 
sinking.  An  intravenous  injection  at  the  end  of  a  month  of  this 
brought  down  the  temperature  to  normal  with  startling  suddenness, 
and  it  stayed  down  for  more  than  a  month.  The  glands,  which  had 
been  swollen,  soft,  and  tender,  shrank  and  became  hard  and  almost 
invisible,  and  the  general  improvement  may  be  gauged  by  the  fact  that 
he  gained  10  lb.  in  weight,  and  walked  out  of  hospital  to  go  to  the 
country.  Soon  after,  however,  the  fever  returned.  Subsequent  intra- 
venous injections  of  salvarsan  always  brought  down  the  temperature 
and  reduced  the  size  of  the  glands,  but  for  successively  shorter  periods. 
An  intramuscular  injection  had  no  effect. 

In  several  subsequent  cases  we  have  tried  salvarsan,  always  with 
benefit.  In  one  case,  a  child  aged  9,  in  which  the  diagnosis  had  been 
confirmed  by  microscopic  examination  of  an  excised  gland,  the  lympho- 


236  LYMPHADENOMA— HODGKIN'S   DISEASE 

mata  entirely  disappeared  after  two  injections  with  an  interval  of  a 
month.  In  another  case  with  enlarged  mediastinal  glands  as  revealed 
by  X-rays,  and  enlarged  superficial  cervical  glands  (examined  micro- 
scopically), a  complete  return  to  normal  followed  the  use  of  salvarsan. 

Our  present  practice  is  to  give  salvarsan  intravenously  as  soon  as 
the  diagnosis  is  made,  and  repeat  it  at  regular — say,  three-monthly — 
intervals  for  a  year  or  two. 

Both  in  estimating  the  effect  of  treatment  and  the  likelihood  of 
success  in  it,  it  is  very  important  to  remember  that  enlargement  of 
superficial  glands  in  the  neck,  axilla,  and  groin  may  be  merely  the  ter- 
mination of  a  process  which  has  begun  in  internal  glands,  and  not,  as  is 
too  often  assumed,  a  primary  enlargement.  A  minute  examination  of 
the  chest  and  abdomen  should  be  made  in  every  case,  and  radiography 
is  often  very  helpful,  especially  in  the  chest.  We  have  seen  very  few 
cases  at  so  early  a  stage  that  the  glandular  enlargement  in  neck  or 
axilla  was  not  already  associated  with  the  presence  of  masses,  large  or 
small,  in  the  mediastinum. 

Literature 

A  full  list  of  references  is  given  by  Ziegler,  Hodgkinsche  Krankheit,  Fischer, 
Jena,  1911.     See  also  Practitioner,  1911. 

References  to  bacteriology  are  given  in  the  text. 


CHAPTER  XXIII 

MULTIPLE   MYELOMA 

Multiple  myeloma  was  first  described  by  Kahler  in  1889.  The  disease 
consists  in  the  formation  of  tumours  (either  circumscribed  or  diffuse)  in 
the  bone-marrow,  associated  with  pain  and  often  with  deformity,  and  in 
a  large  proportion  of  cases  with  the  occurrence  of  a  peculiar  protein 
in  the  urine. 

Etiology. — Cases  have  occurred  at  all  ages  between  twenty-four  and 
seventy-two,  but  it  is  most  common  between  the  ages  of  forty  and 
sixty.  Trauma  has  been  suggested  as  a  causal  factor  in  a  few  cases,  but 
it  is  difficult  to  exclude  the  probability  that  the  injury  merely  attracted 
attention  to  the  illness. 

Pathology. — The  bones  most  commonly  affected  are  the  ribs,  sternum, 
cranial  bones,  and  the  vertebrae.  The  long  bones  are  less  frequently 
involved.  The  tumours  are  usually  circumscribed  masses,  but  diffuse 
infiltration  also  occurs.  They  may  be  of  any  colour  from  white  to 
brownish  red.  Their  consistency  is  usually  rather  greater  than  that 
of  the  marrow.  The  tumour  growth  may  lead  to  rarefaction  of  the 
bone  and  spontaneous  fracture  may  result. 

Microscopically  the  picture  is  an  active  proliferation  of  one  or  other 
of  the  types  of  cell  found  in  the  marrow.  The  growth  presents  the 
general  characters  of  sarcoma,  but  while  its  aggressiveness  towards  the 
marrow  is  very  great,  it  shows  little  tendency  to  involve  neighbourino- 
structures,  and  does  not  invade  blood-vessels. 

As  regards  finer  structure  the  tumours  are  not  the  same  in  all  cases, 
and  the  following  have  been  distinguished : — 

1.  Lymphocytoma. 

2.  Myeloblastoma. 

3.  Myelocytoma. 

4.  Plasmacytoma. 

In  addition  to  these  Pdbbert  has  described  a  case  as  erythroblastoma, 
but,  so  far,  this  is  an  isolated  observation. 

237 


238  MULTIPLE   MYELOMA 

Symptoms. — The  first  symptom  noticed  is  either  the  presence  of  a 
tumour  or  the  occurrence  of  pain.  The  latter  is  always  prominent,  and 
may  lead  to  a  mistaken  diagnosis  of  rheumatism.  It  is  often  associated 
with  tenderness.  The  tumour  growth  may  lead  to  great  deformity. 
There  is  sinking  in  of  the  chest  and  great  kyphosis,  and  it  is  commonly 
remarked  that  the  patient's  stature  decreases.  Spontaneous  fractures 
of  ribs  and  even  of  long  bones  have  occurred.  There  is  a  loss  of  appetite, 
and  as  the  disease  progresses  there  may  be  marked  cachexia.  Fever  is 
an  occasional  symptom.  In  some  cases  there  is  moderate  enlargement 
of  the  spleen  and  lymphatic  glands. 

There  is  always  some  degree  of  anaemia.  Haemoglobin  may  fall  as 
low  as  15  per  cent.  In  a  few  cases  normoblasts  and  megaloblasts  have 
been  found  in  the  blood.  There  is  no  constant  change  in  the  number 
or  proportions  of  the  white  cells.  In  a  few  cases  there  has  been  rather 
a  high  percentage  of  lymphocytes,  and  myelocytes  have  occurred. 

In  rather  less  than  50  per  cent,  of  cases  there  occurs  a  special  protein 
(Bence  Jones'  albumose)  in  the  urine.  This  substance  coagulates  when 
heated  to  between  40°  and  60°  C.  and  passes  into  solution  again  when 
further  heated.  Dissolved  in  salt  solution,  etc.,  it  gives  the  typical 
reactions  of  albumose. 

Nervous  symptoms  may  develop.  Subjective  sensations  such  as 
headache  and  loss  of  memory  are  common.  Hyperesthesia  may  occur, 
and  there  is  progressive  diminution  of  reflex  response  to  stimuli.  Owing 
to  tumour  formation  and  deformity  there  may  be  compression-myelitis 
with  corresponding  symptoms. 

Course. — The  condition  is  progressive  in  the  great  majority  of  cases. 
In  Kahler's  case  there  were  long  remissions.  The  average  duration  of 
the  illness  is  about  one  year,  but  the  disease  may  end  fatally  in  as  short 
a  time  as  six  weeks  or  may  last  for  eight  years.  Death  results  from 
cachexia  and  exhaustion,  from  pressure  by  the  tumours,  or  from  inter- 
current affections  such  as  hypostatic  pneumonia. 

Diagnosis. — In  typical  cases  with  pain,  deformity  and  tumours, 
spontaneous  fractures,  cachexia,  and  anaemia  the  diagnosis  is  easy.  In 
atypical  cases  it  may  be  difficult  or  impossible.  During  life  the  con- 
dition cannot  be  distinguished  with  certainty  from  other  forms  of 
skeletal  tumour  (chondrosarcoma,  myelosarcoma,  or  endothelioma). 

The  presence  of  Bence  Jones'  albumosuria  tends  to  confirm  the 
diagnosis  in  typical  cases,  but  it  must  be  remembered  that  it  is  very 


MULTIPLE   MYELOMA  239 

frequently  absent  and  that  it  occurs  in  a  few  other  conditions.  Thus 
its  presence  has  been  noted  in  myx oedema,  lymphatic  leukaemia,  gastric 
carcinoma  with  bone-marrow  metastases,  toxic  nephritis,  and  in  one 
case,  after  amputation  of  the  leg. 

Examination  by  the  Eontgen  rays  may  aid  in  diagnosis.  The  bones 
appear  somewhat  rarefied  but  the  tumours  are  shown  as  multiple  dark 
masses. 

Literature 

Hirschfeld,  Folia  Ilcematologica,  ix.  1  Teil,  1910,  1.  Williams,  Evans 
and  Glynn,  Lancet,  12th  November  1910.  Hopkins  and  Savory,  Joum.  of 
Physiology,  xlii.  1911,  "A  Study  of  Metabolism  and  of  the  Bence  Jones 
Protein." 


CHAPTEE  XXIV 

HEMOPHILIA 

Definition. — A  disease,  usually  congenital,  characterised  by  a  tendency 
to  haemorrhage,  either  spontaneous  or  associated  with  wounds. 

Etiology. — The  disease  is  congenital  in  the  great  majority  of  cases. 
It  must  probably  be  admitted  that  de  novo  cases  occur.  We  have 
certainly  seen  cases  in  which  no  family  history  could  be  obtained,  but 
in  some  cases  it  is  not  possible  to  get  a  family  history  of  any  kind,  and 
another  difficulty  arises  from  the  fact  that  the  congenital  tendency  may 
pass  over  several  generations  and  break  out  again.  The  tendency  is 
generally  found  in  the  male  sex,  and  doubt  has  been  expressed  whether 
true  haemophilia  ever  occurs  in  the  female.  The  condition  may,  how- 
ever, be  definitely  stated  to  occur  in  females,  and  one  female  case  has 
come  under  our  own  notice. 

Erankel  and  Bohm  publish  a  table  of  151  cases  recorded  as  occur- 
ring in  women.  In  twenty-nine  of  these  the  bleeding  was  on  no 
occasion  from  the  genital  tract. 

The  hereditary  transmission  and  the  sex  incidence  of  the  condition 
are  remarkable.  The  disease  usually  affects  men,  but  the  tendency  to 
the  disease  is  transmitted  through  the  female  line.  Exceptions  to  this 
rule  occasionally  occur.  The  tendency  has  been  transmitted  from  father 
to  son  although  the  mother  was  healthy  and  came  of  a  non-haemophilic 
stock,  and  the  tendency  has  been  transmitted  through  the  father 
although  the  father  himself  had  escaped  the  disease.  Another  remark- 
able fact  regarding  haemophilics  is  their  fecundity.  Several  genealogies 
have  been  published  which  trace  the  disease  through  as  many  as  seven 
generations.  We  give  two  genealogies,  one  fairly  typical,  for  which  we 
are  indebted  to  Dr.  T.  Y.  Finlay,  and  a  curious  atypical  history  which 
came  under  our  own  notice.1 

1  Bulloch  and  Fildes  give  over  200  "typical"  histories. 


240 


HAEMOPHILIA 


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nzniivAurxii-Liiii. 
Genealogy  II. 

M 

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M 

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F 

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M 

In  each  case  the  letter  M  indicates  a  male,  F  a  female.  In  no  case  was 
there  intermarriage  with  a  hsemophilic  stock.  The  female  of  the  second 
generation  in  Genealogy  I.  was  married  twice  and  gave  birth  to  hsemophilics 
by  both  husbands. 

A  single  line  under  the  letter  denotes  symptoms  of  haemophilia ;  a  double 
line  indicates  that  the  person  died  of  haemophilia ;  the  dotted  lines  indicate  a 
slight  degree  of  hsemorrhagic  tendency. 

The  disease  rarely  shows  itself  before  the  first  twelve  months  of  life 
have  elapsed.  This  is  probably  to  be  explained  by  the  amount  of  care 
which  usually  surrounds  the  infant  before  that  age.  At  the  same  time 
it  is  quite  likely  that  many  cases  of  haemorrhage  occurring  either  imme- 
diately or  three  or  four  days  after  birth  are  of  this  nature,  and  cases 
have  occurred  in  which  hsemorrhage  soon  after  birth  has  been  followed 
by  symptoms  of  haemophilia  in  later  life.  Addis  quotes  Nacke  of 
Kirchheim  as  stating  that  he  could  usually  say  at  birth  which  members 
of  the  well-known  bleeder  family,  Mampel,  would  be  haemophilics,  from 
the  bleeding  which  took  place  from  the  cord  even  after  it  had  been 
firmly  ligatured.  Several  members  of  the  family  had  died  of  such 
haemorrhage.  Care  must  be  taken  to  exclude  cases  of  haemorrhage 
from  the  cord  due  to  sepsis.  In  many  instances  there  is  a  distinct 
tendency  to  improvement  in  the  symptoms  any  time  after  the  adolescent 
period.  In  several  cases  in  our  experience  the  tendency  has  entirely 
died  out  after  the  age  of  twenty,  thirty,  or  forty. 

Eace  seems  to  have  no  special  influence,  although  it  has  been  stated 
that  Jews  are  specially  liable  to  haemophilic  symptoms.  It  is  possible 
that  the  rite  of  circumcision  may  reveal  the  tendency  in  Jews  at  an 
unusually  early  age.  Social  condition  does  not  seem  to  have  any 
influence  on  etiology.  Cold  and  damp  surroundings  seem  to  favour  the 
incidence  of  haemorrhagic  symptoms. 


HEMOPHILIA  243 

Pathology. — Apart  from  changes  directly  due  to  haemorrhage,  there 
is  no  demonstrable  structural  lesion  to  account  for  the  disease.  Undue 
thinness  of  vessel  walls  and  a  disproportion  between  the  sectional  area 
of  the  vessels  and  the  volume  of  blood  are  among  the  conditions  which 
have  been  regarded  as  causal  conditions,  but  these  views  have  been 
discarded  by  almost  all  recent  writers.  There  is  a  general  consensus 
of  opinion  that  the  main  factor  in  the  production  of  the  disease  is  a 
diminished  coagulability  of  the  blood.  This  is  regarded  as  the  sole  cause 
by  most  recent  observers,  but  an  undue  friability  of  the  capillaries  is 
regarded  as  an  additional  factor  by  some  writers.  There  can  be  little 
doubt  that  friability  of  the  capillaries  is  a  cause  of  haemorrhage,  and 
in  some  people  bruising  is  very  easily  produced  although  the  coagula- 
bility of  their  blood  is  normal.  But  Morawitz  and  Lossen  have  given 
strong  evidence  that  friability  of  capillaries  is  not  greater  than  usual 
in  hemophilics.  They  connected  a  cupping-glass  with  a  mercurial 
manometer  and  noted  the  amount  of  negative  pressure  which  was 
necessary  in  order  to  produce  bruising  in  normal  persons  and  then 
found  that  just  as  much  suction  was  necessary  to  produce  bruising  in 
the  subjects  of  haemophilia.  It  seems  a  little  difficult  to  conceive  the 
amount  of  damage  that  may  be  done  to  capillaries  in  the  course  of 
moderate  exertion  and  exposure  to  slight  external  violence  if  the  bruis- 
ing that  occurs  in  haemophilia  may  be  taken  as  an  index  of  the  damage. 
We  have  in  view  the  case  of  a  young  hemophilic  who  persisted  in 
indulging  in  dancing,  and  who  was  invariably  covered  with  bruises  as  a 
result.  At  the  same  time  it  seems  probable  that  moderate  injury  does 
cause  rupture  of  capillaries,  and  that  in  healthy  persons  the  rupture 
is  sealed  up  almost  at  once  by  coagulation  of  the  blood,  while  in  hsemo- 
philics the  rupture  is  followed  by  a  variable  and  frequently  considerable 
amount  of  haemorrhage. 

Before  discussing  the  different  theories  of  the  pathology  of  haemo- 
philia in  more  detail  it  may  be  desirable  to  give  a  brief  resume-  of 
modern  views  on  the  coagulation  of  mammalian  blood  in  health. 

Coagulation  of  the  Blood. — The  researches  of  Morawitz  and  Mellanby  have 
done  much  to  throw  light  on  this  subject. 

When  blood  clots  a  soluble  constituent  of  the  plasma  (fibrinogen)  is  split 
up  into  an  insoluble  substance  (fibrin)  and  a  small  amount  of  another  (soluble) 
globulin.  The  fibrin  occurs  in  the  form  of  threads,  which  contract  and 
entangle  the  corpuscles,  thereby  forming  a  "  clot."  This  clot  contracts  and 
from  it  there  exudes  a  clear  straw-coloured  fluid  (serum). 

Solutions  of  fibrinogen  do  not  coagulate  spontaneously.  A  substance 
known  as  thrombin  is  necessary  to  bring  about  coagulation.     This  substance 


244  HEMOPHILIA 

is  often  called  fibrin  ferment,  but  the  name  is  unfortunate,  since  it  acts 
quantitatively,  i.e.  a  measured  quantity  will  bring  about  the  coagulation  of 
a  definite  quantity  of  fibrinogen  and  no  more.  Now  thrombin,  as  such,  does 
not  exist  in  the  circulating  blood,  but  is  evolved  after  blood  has  been  shed. 
It  is  derived  from  the  interaction  of  three  other  substances — (1)  prothrombin, 
(2)  thrombokinase,  and  (3)  calcium  salts. 

1.  Prothrombin  (thrombogen,  Morawitz;  plasmozym,  Fuld)  is  a  substance 
present  in  circulating  blood.  It  is  always  associated  with  fibrinogen  in 
whatever  way  the  latter  has  been  obtained,  and  the  amount  of  prothrombin 
is  always  proportional  to  the  amount  of  fibrinogen.  Prothrombin  is  in  a 
condition  of  "  adsorption  "  in  the  fibrinogen  molecule,  and  the  only  way  in 
which  a  solution  of  prothrombin  can  be  obtained  free  from  fibrinogen  is  to 
coagulate  the  fibrinogen  by  the  addition  of  pre-formed  thrombin.  Fibrin 
is  then  precipitated  and  the  fluid  which  exudes  contains  prothrombin,  a 
substance  which  has  no  coagulating  power  except  in  the  presence  of  thrombo- 
kinase and  lime  salts. 

2.  Thrombokinase. — Thrombokinase  is  not  found  in  the  circulating  blood 
plasma.  It  is,  however,  present  in  the  formed  elements  of  the  blood  and  in 
the  tissues  generally,  especially  in  those  rich  in  nucleo-protein.  The  greater 
the  quantity  of  thrombokinase  added  to  the  blood  the  more  rapid  is  the 
formation  of  thrombin  from  prothrombin.  Certain  authors  have  regarded 
foreign  bodies,  etc.,  as  essential  "  thromboplastic  agencies."  But  it  has  been 
shown  by  Cramer  and  Pringle 1  that  the  supposed  influence  of  such  agencies 
is  really  due  to  the  blood-plates.  If  blood-plates  are  entirely  removed  by 
passing  oxalate  plasma  through  a  Berkefeld  filter  no  clotting  occurs  on  the 
addition  of  calcium  chloride.  Blood  caught  in  paraffined  tubes  does  not 
clot,  because  the  plates  are  not  disintegrated  as  they  are  when  brought  into 
contact  with  glass. 

3.  Calcium  salts  are  also  essential  for  the  formation  of  thrombin.  They 
have  a  much  more  powerful  action  than  salts  of  the  other  earthy  metals,  so 
that  their  action  is  specific  rather  than  ionic.  They  have  also  an  action  in 
breaking  up  blood-plates  and  thus  liberating  prothrombin. 

Although  thrombokinase  and  lime  are  essential  for  the  formation  of 
thrombin,  they  are  not  required  in  the  process  of  clotting  after  thrombin  has 
been  formed. 

Antithrombin. — In  plasma  there  is  a  substance  which  antagonises  the 
clotting  action  of  thrombin.  When  tissues  are  wounded  thrombokinase  is 
liberated  and  in  its  presence  the  prothrombin  with  the  lime  salts  forms 
thrombin.  Thrombin,  having  a  close  affinity  for  fibrinogen,  quickly  forms 
fibrin,  before  the  thrombin  can  be  antagonised  by  the  antithrombin.  Most 
of  the  thrombin  is  precipitated  with  the  fibrin.  Any  fresh  blood  that  finds 
its  way  into  the  clot  is  coagulated  by  the  thrombin  and  prothrombin  is  set 
free,  but  if  no  more  thrombokinase  reaches  it  no  more  thrombin  is  formed. 
That  part  of  the  thrombin  which  is  not  precipitated  with  the  fibrin  is. 
gradually  neutralised  by  the  antithrombin. 

1  Quart.  Journ.  of  Exper.  Physiol.,  vi.  1913. 


HEMOPHILIA  245 

To  summarise  : 

Thrombokinase    (  Prothrombin  ^| 
causes  the      -!          and         >  to  produce  Thrombin. 
union  of        I  Limi  Salts    J 

Thrombin  converts  fibrinogen  into  fibrin. 
Antithrombin  inactivates  excess  thrombin. 

Howell  interprets  the  interaction  of  these  substances  rather  differently. 
He  holds  that  prothrombin  may  be  converted  to  active  thrombin  by  the 
action  of  lime  alone.  This  activation  does  not  occur  in  the  circulating  blood, 
because  antithrombin  is  present  in  sufficient  amount  to  prevent  the  reaction. 
In  shed  blood  the  tissue  cells  or  blood-cells  and  plates  furnish  a  thrombo- 
plastic  substance  which  neutralises  the  action  of  the  antithrombin  and  thus 
permits  the  calcium  to  react  with  the  prothrombin  to  form  thrombin,  which 
in  turn  reacts  with  fibrinogen  to  form  fibrin. 

Sahli  regards  haemophilia  as  a  cellular  anomaly  both  of  the  blood 
corpuscles  and  of  the  endothelial  cells.  Blood  does  not  coagulate  readily, 
because  there  is  a  deficiency  of  thrombokinase  in  the  blood  and  vascular 
endothelium.  A  clot  may  form  when  extravasated  blood  comes  in  con- 
tact with  the  tissues  where  there  is  thrombokinase,  but  in  spite  of 
this  clot  bleeding  may  continue  because  no  clot  forms  in  the  ruptured 
vessels  themselves.  Normal  blood  corpuscles  have  a  powerful  action  in 
increasing  the  coagulability  of  hemophilic  blood,  although  hemophilic 
corpuscles  have  much  less  effect. 

Morawitz  and  Lossen  ascribe  hemophilia  to  a  deficiency  of  thrombo- 
kinase in  the  tissues  in  general,  and  find  that  the  addition  of  thrombo- 
kinase to  hemophilic  blood  causes  a  rapid  coagulation. 

Weil  describes  two  forms  of  hemophilia,  a  family  form  and  an 
accidental  or  sporadic  form.  In  the  former  he  holds  that  the  essential 
pathology  is  an  excess  of  antifibrin  ferment  (antithrombin),  and  in 
the  latter  he  considers  that  the  error  consists  in  a  deficiency  of  the 
constituents  of  thrombin. 

Nolf  and  Herry  consider  that  the  interaction  of  fibrinogen,  pro- 
thrombin, and  thrombozyme  (thrombokinase)  with  lime  gives  origin  to 
fibrin  and  thrombin.  Thrombozyme  is  not  found  in  tissues  generally 
but  is  abundant  in  leucocytes,  blood-plates,  and  vascular  endothelium. 
The  blood  thus  contains  all  the  elements  necessary  for  the  formation  of 
clot.  It  remains  fluid  in  the  vessels  because  the  liver  produces  anti- 
thrombin, and  in  normal  conditions  there  is  an  equilibrium  which 
maintains  fluidity.  In  certain  intoxications  the  liver  may  secrete  this 
antithrombin  in  great  excess,  but  this  is  not  a  factor  in  producing 
hemophilia.     The  cause  of  hemophilia  is  the  functional  insufficiency 


246  HAEMOPHILIA 

of  thrombozyme.  The  vascular  endothelium  plays  a  large  part  in 
secreting  thrombozyme,  and  along  with  this  deficiency  there  is  an 
associated  friability  which  accounts  for  the  many  slight  accidental 
haemorrhages  in  haemophilia  which  are  not  accounted  for  by  mere 
incoagulability  of  the  blood. 

Addis  finds  that  coagulation  time  is  delayed,  and  that  the  fault  lies 
in  the  slow  formation  of  thrombin  rather  than  in  the  interaction  between 
thrombin  and  fibrinogen  once  thrombin  has  been  formed.  The  rate  of 
formation  of  thrombin  in  haemophilia  is  unduly  slow.  He  could  find 
no  evidence  of  the  presence  of  any  substance  inhibiting  coagulation. 
It  is  not  possible  to  obtain  as  short  a  coagulation  time  in  hsemophilic 
as  in  normal  blood  by  the  addition  of  any  amount  of  calcium.  When 
large  amounts  of  thrombokinase  were  added  the  coagulation  time  in 
both  normal  and  hemophilic  blood  became  very  rapid.  When  only 
small  quantities  were  added  the  characteristic  delay  in  the  case  of 
hsemophilic  blood  again  became  evident.  When  the  amount  of  thrombo- 
kinase in  normal  and  in  hsemophilic  blood  was  compared  there  was  no 
difference.  A  deficiency  in  thrombokinase  is  therefore  not  the  cause. 
There  was  no  quantitative  deficiency  of  prothrombin  but  a  qualitative 
difference  was  found,  inasmuch  as  it  showed  a  very  slow  rate  of  change 
into  thrombin  in  the  presence  of  calcium  and  thrombokinase.  It  was 
found  that  the  addition  of  a  very  small  quantity  of  normal  prothrombin 
greatly  accelerated  the  coagulation  of  hsemophilic  plasma,  whereas  the 
addition  of  an  equal  quantity  of  hsemophilic  prothrombin  had  no  effect. 
Addis  therefore  ascribes  haemophilia  to  an  inherited  anomaly  in  the 
construction  of  the  prothrombin  of  the  blood  which  reveals  itself  in  the 
unduly  long  time  required  for  its  activation. 

Addis's  researches  go  far  to  explain  some  of  the  curious  phenomena 
of  the  disease,  such  as  the  occasional  persistence  of  bleeding  from  a  small 
wound  and  comparatively  slight  haemorrhage  from  a  larger  wound,  and 
the  fact  that  bleeding  frequently  continues  although  a  clot  may  be 
present.  When  a  wound  is  made  blood  escapes  and  fills  the  cavity. 
Thrombokinase  from  the  injured  tissues  mixes  with  the  blood  which  is 
in  contact  with  the  sides  of  the  wound.  A  layer  of  fibrin  may  thus  be 
deposited  on  the  sides  of  the  wound,  but  in  the  more  centrally  situated 
blood  the  concentration  of  thrombokinase  is  not  so  great.  Owing  to  the 
delay  in  the  formation  of  thrombin  this  part  of  the  blood  is  driven  out 
of  the  wound  before  sufficient  thrombin  has  been  formed  to  coagulate  it. 
It  must  be  remembered  that  thrombin  acts  quantitatively,  and  that 
although  a  small  quantity  may  pass  from  the  periphery  of  the  wound 


HAEMOPHILIA  247 

towards  the  centre,  it  may  cause  a  mere  partial  loose  coagulum  through 
which  blood  may  trickle,  washing  away  any  thrombokinase  (which 
now  reaches  it  with  difficulty  through  the  fibrin  layer  over  the  surfaces 
of  the  wound)  before  it  has  time  to  convert  the  prothrombin  into 
thrombin. 

We  consider  that  delayed  coagulability  of  the  blood  is  probably  the 
sole  factor,  and  is  certainly  the  most  important  factor  in  the  production 
of  haemophilia,  and  that  in  our  opinion  the  most  convincing  view  of  the 
cause  of  the  delayed  coagulability  is  that  of  Addis. 

Symptoms. — The  subjects  of  haemophilia  are  usually  fair,  with  good 
complexions.  The  muscles  are  generally  not  powerful,  and  there  is  a 
fair  but  not  excessive  development  of  subcutaneous  fat. 

Prodromal  Symptoms. — Prodromal  symptoms  have  been  described 
in  many  instances  as  indicating  that  a  haemorrhage  was  imminent. 
Symptoms  of  plethora,  headaches  and  palpitation,  and  a  sense  of  tight- 
ness have  been  described  in  this  connection.  Such  symptoms  are 
exceedingly  rare.  We  can  recall  one  case  occurring  in  a  student  of 
medicine  who  assured  us  that  he  could  always  foretell  an  attack  of 
haemorrhage  (usually  epistaxis)  by  a  feeling  of  special  "  fitness  "  for  a 
few  days  previously. 

Hemorrhagic  Symptoms. — The  haemorrhagic  symptoms  may  con- 
veniently be  divided  into  external,  internal  and  interstitial,  and 
synovial. 

External  Haemorrhages. — The  external  haemorrhages  may  be  spon- 
taneous but  are  more  usually  associated  with  wounds.  By  far  the 
most  common  spontaneous  haemorrhage  is  epistaxis.  According  to 
Grandidier  the  next  most  common  sites  in  order  are  the  gums,  stomach, 
intestines,  urethra,  and  lungs.  Much  less  common  are  haemorrhages 
from  the  skin  of  the  head,  tongue,  finger-tips,  tear-papilla,  eyelids, 
external  ear,  vulva,  umbilicus,  and  scrotum.  Most  female  haemophilics 
do  not  suffer  from  excessive  haemorrhage  in  connection  with  menstrua- 
tion and  parturition,  but  in  some  cases  the  former  function  leads  to  a 
degree  of  anaemia  which  is  barely  recovered  from  before  the  next  period 
is  due. 

Traumatic  haemorrhages  are  specially  dangerous  in  haemophilia. 
Patal  bleeding  has  followed  the  extraction  of  a  tooth  or  circumcision. 
Long-continued  haemorrhage  may  follow  trivial  scratches,  and  a  shaving 
cut  is  a  contingency  which  may  play  havoc  with  morning  engagements. 
We  knew  a  haemophilic  farmer  who  for  this  reason  always  shaved  on 


248  HiEMOPHILIA 

the  evening  before  a  market-day.  The  bleeding  is  a  capillary  oozing, 
which  may  persist  for  hours  or  days.  It  may  continue  in  spite  of  the 
formation  of  large  masses  of  clot,  and  in  connection  with  epistaxis  and 
bleeding  from  other  mucous  surfaces  large  loose  adherent  clots  com- 
monly occur.     These  may  decompose  and  give  rise  to  great  discomfort. 

Punctures  into  the  skin  do  not  bleed  unduly  freely  owing  to  the 
sealing  of  the  wound  by  the  elasticity  of  the  tissues.  In  taking  samples 
of  blood  for  examination  it  is  better  to  puncture  the  finger  than  the  ear, 
and  in  severe  cases  it  might  be  well  to  use  a  round  needle  instead  of  one 
with  cutting  edges.  Puncture  of  a  vein  is  also  a  safe  proceeding,  as  the 
elastic  wall  at  once  retracts  and  closes  the  wound  made  by  a  small 
needle. 

A  curious  fact  is  the  varying  liability  to  haemorrhage  at  different 
times.  At  one  time  slight  pressure  with  a  finger  may  be  followed  by  a 
large  ecchymosis,  while  a  week  later  a  much  more  severe  injury  seems 
to  have  no  specially  bad  effect. 

Internal  Haemorrhage.  —  Petechial  haemorrhages  are  not  common. 
Very  extensive  effusions  may  occur  in  connection  with  slight  pressure. 
Muscular  action  may  be  sufficient  to  cause  hsemorrhage.  Large  hserna- 
tomata  may  result  and  may  be  absorbed  in  time,  but  instances  have 
occurred  of  calcification  of  the  effused  blood.  Along  with  the  effusion 
there  may  be  great  pain,  and  paralysis  of  nerves  may  result.  Blood 
may  be  effused  into  the  stomach  and  bowel,  and  the  presence  of  large 
decomposing  clots  may  lead  to  marasmus  and  death.  Hsemorrhage  in 
the  serous  sacs  and  into  the  meninges  is  rare.  A  few  cases  of  fracture 
of  the  long  bones  in  haemophilias  have  been  reported.  There  is  very 
great  swelling  and  the  temperature  rises.  There  seems  to  be  no  delay 
in  union. 

Joint  Hcemorrhages. — Any  joint  may  may  be  affected.  The  order  of 
frequency  with  which  the  joints  are  affected  is  knee,  ankle,  wrist,  elbow, 
hip.  The  swelling  comes  on  suddenly  and  is  always  associated  with 
pain.  As  a  result  of  the  hsemorrhage  and  tension  there  may  be  inflam- 
mation, and  the  effused  fluid  blood  gives  rise  to  fluctuation.  The 
temperature  rises  and  a  mistaken  diagnosis  is  readily  made.  The 
future  history  of  the  joint  varies.  The  effused  blood  may  rapidly 
disappear.  There  may  be  repeated  serous  or  hsemo-serous  effusions. 
Arthritis  is  a  common  sequel,  and  in  such  a  case  the  clot  is  specially 
liable  to  become  organised  by  fibrous  tissue  passing  in  from  the  synovial 
membrane  and  the  joint  may  undergo  firm  fibrous  anchylosis.  Lipping 
of  the  joint  and  erosion  of  the  cartilage  may  occur,  leading  to  a  condition 


HAEMOPHILIA  249 

of  arthritis  deformans.     Volkmann's  contracture  is  sometimes  a  sequel 
of  joint  injury. 

Blood  Changes. — Apart  from  the  delayed  coagulation  time  there  is 
no  change.  The  number  of  red  corpuscles,  white  cells,  and  plates  shows 
no  abnormality  until  haemorrhage  has  given  rise  to  anaemia.  Owing  to 
the  gradual  and  prolonged  nature  of  the  haemorrhage  leucocytosis  is  not 
often  noticed.  The  proportions  of  the  leucocytes  are  not  altered.  In 
one  of  our  cases  which  ended  fatally  from  epistaxis  and  bleeding  from 
the  gums  the  red  cells  on  the  day  before  death  numbered  295,000  per 
c.nim.,  the  leucocytes  numbered  4400,  there  were  64  per  cent,  of  poly- 
morphs and  a  few  normoblasts. 

Diagnosis. — Perhaps  the  family  history  is  the  most  important  diag- 
nostic criterion.  Another  important  point  is  that  the  haemorrhage  is 
generally  associated  with  trauma.  Even  in  the  so-called  spontaneous 
haemorrhages  it  will  be  found  that  it  is  hardly  possible  to  exclude  the 
possibility  of  some  force  having  been  applied  to  the  seat  of  haemorrhage. 
This  point  will  serve  in  many  cases  to  distinguish  the  condition  from 
purpura,  in  which  the  haemorrhages  are  usually  multiple  and  occur  in 
many  instances  in  sites  which  are  not  likely  to  have  had  pressure  or 
violence  applied  to  them.  A  diminished  coagulability  of  the  blood 
favours  the  likelihood  of  haemophilia. 

Mistakes  are  most  likely  to  arise  in  connection  with  the  joint 
affections,  more  particularly  as  the  condition  is  rare.  It  is  important 
from  the  point  of  view  of  treatment  that  a  haemophilie  joint  affection 
should  not  be  overlooked.  On  the  other  hand,  a  mistaken  diagnosis  of 
haemophilia  in  a  case  of  recurring  epistaxis  or  haematuria  will  have  no 
ill  effect  upon  the  patient,  although  in  course  of  time  it  may  affect  the 
reputation  of  the  practitioner. 

Prognosis.  —  This  is  always  grave,  especially  in  young  subjects. 
After  early  childhood  the  risk  is  less,  possibly  because  the  child's 
attendants  have  learned  to  take  special  care ;  but  there  is  often  a 
real  diminution  in  the  bleeding  tendency.  The  outlook  is  more 
serious  in  boys  than  girls.  Grandidier  states  that  of  152  boy  haemo- 
philics,  81  died  before  the  termination  of  the  seventh  year.  In  most 
cases  the  tendency  diminishes  as  age  advances,  and  in  many  of  the  sur- 
viving cases  it  has  disappeared  by  the  age  of  twenty  or  later.  On  the 
other  hand,  patients  with  marked  haemophilie  symptoms  have  reached 


250  HEMOPHILIA 

mature  age  with  the  tendency  persisting.  Menstruation  and  parturition 
do  not  add  greatly  to  the  risk  to  life  in  the  great  majority  of  cases,  but 
in  a  few  cases  menstruation  is  a  source  of  recurring  anxiety. 

Treatment. — General. — Hemophilic  children  must  be  watched  with 
great  care,  in  order  that  even  minor  accidents  may  be  avoided. 
Teachers  and  others  in  charge  of  such  children  should  be  warned  of 
the  existence  of  the  condition.  Charges  against  teachers  of  excessive 
corporal  punishment  in  the  case  of  hemophilics  are  by  no  means 
unknown. 

The  choice  of  occupation  is,  of  course,  considerably  restricted. 
Dentists  and  doctors  should  be  informed  of  the  existence  of  the  ten- 
dency in  the  patient  or  in  any  of  the  members  of  the  family.  Females 
of  a  hemophilic  stock  should  be  advised  not  to  marry.  This  also  applies 
to  male  bleeders.  The  more  remote  possibility  of  transmitting  the 
disease  may  be  pointed  out  to  non-hemophilic  males  of  a  hemophilic 
stock,  the  actual  risk  in  such  cases  being  determined  by  a  survey  of  the 
whole  family  history. 

In  hemophilia  the  bowels  should  be  carefully  regulated,  and  articles 
of  diet  or  luxury  which  have  any  tendency  to  cause  disturbance  of  the 
vascular  system  should  be  used  only  with  the  greatest  care.  Kesidence 
in  warm  climates  seems  to  lessen  the  tendency  to  bleed  in  some  cases. 

Medicinal  Treatment.  —  Calcium  salts  have  been  strongly  recom- 
mended, but  probably  on  insufficient  grounds.  In  estimating  the 
effect  of  remedies  the  tendency  of  the  symptoms  to  vary  from  time 
to  time  has  to  be  remembered.  Addis  has  demonstrated  that  the 
amount  of  calcium  which  can  be  added  to  the  blood  is  less  than  the 
amount  necessary  to  affect  coagulation.  At  the  same  time  it  can  do  no 
harm,  and  "Wright  has  strongly  recommended  a  mixture  of  equal  parts 
of  calcium  lactate  and  magnesium  carbonate,  checked  by  observations 
on  the  coagulability  of  the  blood.  Wright  has  also  advocated  the 
inhalation  of  carbon  dioxide. 

Gelatine  (5  per  cent.)  injections  have  been  tried,  but  reports  on  its 
efficacy  are  contradictory,  and  in  some  cases  toxic  symptoms  have 
followed  its  use,  as  well  as  disasters  from  imperfect  sterilisation. 
Gelatine  can  be  administered  without  danger  by  the  mouth,  and  benefit 
has  been  alleged  to  follow  its  use. 

Grant,  arguing  from  the  rarity  of  the  condition  in  females,  adminis- 
tered ovarian  extract  with  beneficial  effect  in  one  case.  Among  a  host  of 
other  substances  which  have  been  employed  are  raw  meat  juice,  thyroid 


HAEMOPHILIA  251 

extract,  ergot,  adrenalin,  turpentine,  perchloride  of  iron,  and  practically 
all  the  drugs  which  have  any  styptic  effect. 

Serum  Treatment. — There  is  fortunately  a  consensus  of  opinion,  even 
among  those  who  differ  regarding  the  explanation  of  the  delayed  coagu- 
lation time,  that  benefit  results  from  serum  treatment,  which  was  intro- 
duced by  Weil.  Fresh  serum  from  the  horse,  rabbit,  or  man  may  be 
used.  Ox  serum  should  not  be  employed,  as  it  may  cause  severe  symp- 
toms of  headache,  vomiting,  rigors,  and  cyanosis.  The  serum  may  be 
given  by  the  mouth,  but  is  more  effective  when  administered  hypo- 
dermically  or  intravenously.  The  latter  method  is  to  be  preferred  as 
being  more  efficacious.  The  injection  can  be  made  into  a  vein  without 
any  damage  to  tissues,  and  the  puncture  is  sealed  by  the  elasticity  of 
the  tissues,  while  a  hypodermic  injection  almost  invariably  leads  to 
ecchymosis  or  the  formation  of  a  hsematoma.  The  dose  of  serum  is 
20-30  c.c.  hypodermically,  or  10-20  c.c.  intravenously.  A  reduction 
should  be  made  in  the  case  of  children. 

While  fresh  serum  is  always  to  be  preferred  when  it  is  available, 
anticliphtheritic  serum,  or  the  horse  serum  which  is  now  supplied  by 
several  firms,  may  be  employed.  It  has  been  stated  that  even  heated 
serum  which  contains  no  thrombin  is  of  service.  Weil  holds  that  the 
effect  of  the  serum  lasts  for  about  a  month.  Labbe  recommends  the 
intravenous  injection  of  serum  once  a  month,  and  says  that  by  this 
means  the  coagulation  time  can  be  brought  to  normal  and  that  surgical 
operations  may  then  be  performed  with  safety.  Nolf  and  Herry,  while 
agreeing  that  serum  does  good  after  it  has  been  absorbed,  suggest  that 
even  better  results  can  be  obtained  by  the  use  of  propeptone.  This 
substance  has  a  double  action,  according  to  these  authors.  If  injected 
rapidly  it  stimulates  the  liver  to  throw  out  a  large  amount  of  anti- 
thrombin,  but  if  injected  slowly  this  stimulation  does  not  occur,  but 
there  is  a  greatly  increased  output  of  thrombozyme  (thrombokinase)  by 
the  leucocytes  and  vascular  endothelium.  A  subcutaneous  injection  of 
10  c.c.  of  a  5  per  cent,  solution  of  Witte's  peptone  in  5  per  cent,  salt 
solution  may  be  given  on  alternate  days.  This  is  said  to  give  good 
results  in  cases  of  rebellious  haemorrhage  from  causes  other  than  hsemo- 
philia.  The  advantages  of  peptone  in  the  matter  of  availability  and  in 
the  ease  with  which  it  can  be  sterilised  are  obvious.  The  only  danger  in 
using  it  is  the  possibility  that  it  may  temporarily  increase  the  severity 
of  the  condition  which  it  is  sought  to  check.  So  far  as  we  know,  Nolf 
and  Herry's  results  have  not  been  confirmed  by  other  writers. 

Local  Treatment. — The  ordinary  measures  for  the  arrest  of  hsemor- 


252  HEMOPHILIA 

rhage  are  of  course  indicated.  The  part  should  be  put  at  rest,  and  if 
possible  fairly  firm  pressure  should  be  applied.  The  presence  of  loose 
clots  in  a  wound  or  bleeding  surface  appears  to  do  more  harm  than  good, 
and  there  may  be  continued  haemorrhage  from  the  centre  of  a  wound 
which  has  a  firm  layer  of  fibrin  attached  to  its  sides.  If  oozing  continues 
in  spite  of  clots  these  should  be  removed,  and  the  surface  should  be 
thoroughly  soaked  with  a  strong  solution  of  thrombokinase,  in  the  form 
of  an  extract  of  lymph  gland,  thymus,  testis,  or  other  source  of  nucleo- 
protein,  made  by  chopping  up  the  organ  in  0"9  per  cent,  saline  solution 
containing  1  per  cent,  of  sodium  carbonate.  Probably  thrombokinase 
from  a  human  source  is  preferable  when  it  can  be  obtained.  Failing 
stronger  solutions,  fresh  human  blood  may  be  used  as  a  source  of  throm- 
bokinase. A  powerful  extract  of  thrombokinase  may  be  prepared  by 
washing  sheep's  fibrin  with  tap  water  till  it  is  free  from  haemoglobin 
and  then  kneading  about  20  grms.  of  the  wet  fibrin  in  300  c.c.  of  dis- 
tilled water  (Buswell 1). 

Addis  reports  the  case  of  a  gradually  increasing  hematoma  in  which 
the  bleeding  was  eventually  stopped  after  incision  and  stripping  away 
a  firm  film  of  fibrin  from  the  wound  surface  and  thereafter  applying 
thrombokinase. 

To  sum  up,  we  may  say  that  the  precautionary  measures  already  dis- 
cussed are  indicated.  The  administration  of  lime  may  possibly  do  good 
and  is  not  likely  to  do  harm.  Intravenous  injection  of  fresh  serum  is 
perhaps  the  most  efficacious  treatment  at  present  known.  The  injec- 
tion of  peptone  appears  worthy  of  further  investigation.  Ordinary  local 
measures  for  the  arrest  of  haemorrhage  should,  if  necessary,  be  supple- 
mented by  the  removal  of  clots  and  the  application  of  a  solution  of 
thrombokinase. 

LlTEEATUKE 

Coagulation 

Schmidt,  Zur  Blutlehre,  Leipzig,  1892  ;  Weitere  Beitrage  zur  Blutlehre, 
Wiesbaden,  1895.  Morawitz,  Hofmeister's  Beitr.,  v.  1903.  Fuld,  Zentralb.  f. 
Physiol,  xvii.  1903.     Mellanby,  Joum.  of  Physiol,  xxxviii.  1908. 

Coagulation  Time 

Addis,  Quart.  Joum.  Exper.  Physiol,  i.  1908;  Edin.  Med.  Joum.,  1910; 
Quart.  Joum.  of  Med.,  ii.  1909. 

lJoum.  of  Physiol,  1913. 


HAEMOPHILIA  253 

Hcemophilia 

Grandidier,  Die  Hdmophilie  oder  die  Bluterhranlcheit,  1855;  Schmidt's 
Jahrlucher  der  Gesammten  Med.,  1877.  Legg,  Treatise  on  Hcemophilia,  1872 ; 
St.  Barts.  Uosp.  Reports,  1881.  Sahli,  Zeitschr.  f.  hlin.  Med.,  1905  ;  Deutscli 
Archiv  f.  hlin.  Med.,  xcix.  5  and  6.  G-oodall,  Scottish  Med.  Joum.,  1905. 
Weil,  Bull,  et  mim.  de  la  Soc.  Mid.  des  Hopitaux  de  Paris,  1908.  Morawitz 
and  Lossen,  Deutsch  Archiv  f.  hlin.  Med.,  1908.  Wright,  Allbutt  and 
Rolleston's  System  of  Med.,  1909.  Nolf  and  Herry,  Revue  de  mid.,  1909  and 
1910.  Addis,  Quart.  Joum.  of  Med.,  1910.  Bulloch  and  Fildes,  Eugenics 
Laboratory  Memoir  XII. — Hcemophilia :  London,  Dulaw  &  Co.,  1911. 


CHAPTEE  XXV 
PUEPUEA— SCURVY— INFANTILE   SCUEVY 

PUEPUEA 

Purpura  is  a  symptom  rather  than  a  disease.  The  condition 
is  characterised  by  extravasations  of  blood  into  the  skin,  and,  less 
commonly,  by  haemorrhages  from  the  mucous  membranes.  The  extra- 
vasations into  the  skin  are  usually  small  spots  about  a  millimetre  in 
diameter  (petechia) ;  sometimes  they  are  considerably  larger  (vibices), 
and  sometimes  they  may  occur  over  large  areas  (ecchymoses).  They  are 
at  first  bright  red  in  colour,  but  fade  through  purple  in  a  day  or  two  and 
eventually  become  a  dull  brown  colour.  Sometimes  they  appear  in 
successive  crops,  so  that  all  stages  are  present  at  the  same  time.  The 
spots  do  not  disappear  on  pressure,  and  are  thus  easily  distinguished 
from  inflammatory  eruptions. 

In  only  a  small  proportion  of  the  cases  is  the  coagulation  time  of 
the  blood  increased,  and  even  in  these  cases  the  diminished  coagulability 
is  to  be  regarded  as  incidental  rather  than  essential.  The  essential 
lesion  is  an  increased  friability  of  the  small  vessels,  possibly  the  small 
veins.  The  vessel  weakness  is  probably  a  multiple  local  lesion,  since 
the  bleeding  in  purpura  is  spontaneous  and  traumatic  bruising  does 
not  occur  unless  there  is  concomitant  diminution  of  the  coagulability 
of  the  blood. 

Varieties. — It  is  impossible  to  give  a  satisfactory  classification  of  the 
causes  of  purpura,  and  even  when  all  the  known  causes  have  been  men- 
tioned there  is  still  a  considerable  group  of  cases  unaccounted  for.  The 
chief  conditions  associated  with  purpura  are  noted  below,  but  it  will  be 
seen  that  the  groups  mentioned  are  not  necessarily  mutually  exclusive. 

1.  Morbid  Conditions  of  the  Blood. — Purpuric  lesions  sometimes  occur 
in  cases  of  pernicious  and  secondary  ansemia  and  in  leucocythsemia, 
especially  in  the  terminal  stages  of  the  chronic  forms,  and  sometimes 
throughout  the  whole  course  of  the  acute  cases.     The  extravasations 

254 


PURPURA— SCUKVY— INFANTILE   SCURVY  255 

which  occur  in  haemophilia  are  not  to  be  regarded  as  purpuric,  since  they 
are  not  usually  spontaneous  and  appear  to  be  solely  due  to  a  defect  of 
coagulation. 

2.  Toxic  Conditions. — (a)  The  most  frequent  cause  of  purpura  is 
rheumatism.  The  extravasations  are  most  common  on  the  legs,  less 
common  on  the  arms,  and  rare  on  the  trunk.  The  haemorrhages  are 
often  associated  with  other  lesions.  A  case  not  uncommonly  begins 
with  manifestations  of  erythema  nodosum  on  the  shins,  and  later, 
extravasations  occur  in  connection  with  the  lesions. 

Schonlein's  Purpura — Poliosis  Pheumatica. — This  condition  is  asso- 
ciated with  a  multiple  arthritis,  not  infrequently  a  sore  throat,  and  a 
raised  temperature  which  may  reach  103°  F.  The  hemorrhagic  rash 
makes  its  appearance  on  the  legs  or  about  the  affected  joints,  and  may 
be  the  only  skin  affection,  but  more  usually  there  are  other  associated 
skin  lesions.  The  most  common  of  these  is  urticaria,  but  vesicles  may 
occur,  sometimes  erythema  nodosum,  and  more  rarely  large  patches  of 
oedema.  The  urine  is  reduced  in  amount  and  may  be  albuminous. 
Some  cases  have  been  associated  with  chorea.  Prognosis  is  good,  but 
there  is  a  tendency  to  relapses. 

(b)  Septicaemia  in  all  its  forms  is  often  associated  with  purpura. 
Any  of  the  exanthemata  may  show  hemorrhagic  rashes,  and  the  con- 
tinued fevers  and  malaria  may  cause  purpura. 

(c)  Gastro- Intestinal  Conditions. — Absorption  of  intestinal  toxins  may 
give  rise  to  purpura. 

Henoch's  Purpura. — This  variety  is  most  commonly  seen  in  children. 
The  purpura  is  often  associated  with  other  cutaneous  lesions  such  as 
erythema.  There  are  sometimes  haemorrhages  from  the  mucous  mem- 
branes. Attacks  of  abdominal  pain,  vomiting,  and  diarrhoea  are  common. 
A  large  number  of  cases  have  been  recorded  in  which  the  purpura  was 
associated  with  intussusception.  There  are  sometimes  slight  pains  or 
swellings  of  the  joints.  Unless  associated  with  a  grave  abdominal  con- 
dition prognosis  is  good,  although  a  few  fatal  cases  have  been  reported. 
Haemorrhage,  nephritis,  and  exhaustion  are  the  special  dangers. 
Relapses  are  not  uncommon,  the  condition  tending  to  recur  for 
several  years. 

(d)  Cirrhosis  of  the  Liver  and  Jaundice. — Jaundice  of  temporary 
character  is  rarely  if  ever  accompanied  by  purpura.  The  longer  jaundice 
lasts  the  more  likely  it  is  to  be  accompanied  by  haemorrhage,  and  there- 
fore it  is  most  common  with  malignant  disease  either  of  the  liver  itself 
or  in  such  a  position  as  to  cause  obstruction  of  the  common  duct.     The 


256  PUEPUEA— SCUEVY— INFANTILE   SCUEVY 

malignant  cachexia  also  plays  a  part  in  its  production.  Purpura  is  not 
uncommon  in  the  late  stages  of  cirrhosis  of  the  liver. 

(e)  Bright's  disease  in  all  its  varieties  and  arteriosclerosis  may  be 
causes  of  purpura,  as  of  other  hemorrhages. 

(/)  Drugs  and  Poisons. — The  chief  causes  of  purpura  under  this 
heading  are  iodide  of  potassium,  chlorate  of  potassium,  copaiba,  bella- 
donna, mercury  and  phosphorus,  fungi,  snake  venom,  and  serum. 

3.  Cachexia. — This  is  a  common  cause  of  purpura.  Among  the  chief 
conditions  there  may  be  mentioned  debility  from  any  cause,  privation, 
congenital  syphilis,  tubercle,  rickets,  and  malignant  disease. 

4.  Mechanical  Conditions. — Whooping-cough,  heart  disease,  epilepsy, 
or  any  condition  leading  to  great  congestion  may  cause  orthostatic 
purpura.     Self-inflicted  injury  may  lead  to  purpura  artifacta. 

5.  Morhid  Conditions  of  the  Nervous  System. — Purpura  has  been 
noted  in  association  with  locomotor  ataxia,  peripheral  neuritis,  myelitis? 
and  hysteria. 

6.  Unknown  Conditions. — Cases  occur  when  none  of  the  above  or 
indeed  any  causal  condition  can  be  discovered. 

Purpura  Simplex. — This  is  a  mild  form  common  in  children.  A 
purpuric  eruption,  usually  petechial,  occurs  on  the  lower  limbs  alone  or 
on  the  limbs  and  trunk.  There  may  be  slight  fever,  loss  of  appetite, 
and  anemia.  Diarrhoea  sometimes  occurs.  Patients  are  usually  well 
within  a  fortnight. 

Purpura  Hemorrhagica — Morbus  Maculosus  (Werlhof). — This  con- 
dition is  one  of  severe  purpura  accompanied  by  hemorrhages  from  the 
mucous  membranes.  It  usually  affects  children  in  delicate  health,  and 
is  more  common  in  girls.  Cases  in  adults  have  been  reported.  Initial 
symptoms  are  indefinite  ill-health  and  weakness.  Purpuric  spots  occur 
on  the  skin  and  increase  rapidly  in  number  and  size.  Bleeding  from 
the  mucous  membranes  begins.  Epistaxis,  bleeding  from  the  gums, 
hematemesis,  hematuria,  and,  less  commonly,  hemoptysis  may  occur. 
The  patient  becomes  rapidly  and  profoundly  anemic.  A  certain  amount 
of  fever  is  usually  present.     Cases  may  terminate  fatally. 

Diagnosis. — Malignant  types  of  fevers,  especially  measles  and  small- 
pox, have  to  be  distinguished  by  the  history,  the  temperature,  and  by 
the  examination  of  the  blood.  Scurvy  is  distinguished  by  the  history, 
the  condition  of  the  gums,  and  the  intramuscular  hemorrhages.  It  is 
of  the  first  importance  to  exclude  the  true  blood  diseases  by  a  proper 
blood  examination. 


PUEPUEA— SCUEVY— INFANTILE   SCUEVY  257 

Prognosis  varies  with  the  cause  and  severity  of  the  condition. 
Cases  of  purpura  fulminans,  occurring  especially  in  children,  may  be 
fatal  within  twenty-four  hours,  sometimes  before  there  has  been  any 
bleeding  from  mucous  membranes.  This  contingency,  however,  is 
fortunately  rare,  and  even  severe  cases  with  multiple  haemorrhages, 
albuminuria,  and  pyrexia  usually  get  well.  In  favourable  cases  the 
bleeding  stops  within  a  fortnight,  but  a  much  longer  time  may  elapse 
before  the  anaemia  is  recovered  from.  There  may.  be  recurring  attacks 
of  epistaxis  after  other  symptoms  have  disappeared. 

The  Blood  Changes. — The  blood  changes  are  in  no  way  characteristic. 
In  mild  cases  there  may  be  no  demonstrable  change ;  in  others  a  marked 
anaemia  may  rapidly  ensue,  even  when  there  has  been  no  actual  haemor- 
rhage from  mucous  membranes.  These  cases  are  not  easily  explained, 
since  the  amount  of  blood  in  the  skin  rashes  is  very  slight,  and  is  indeed 
hardly  noticeable  in  transverse  microscopic  sections  of  the  purpuric  spots. 
In  purpura  hemorrhagica  the  anaemia  may  be  considerable,  and  the 
usual  picture  of  secondary  anaemia  develops,  varying  in  the  usual  way 
according  to  the  degree  of  severity.  The  leucocyte  count  may  show  a 
considerable  transient  increase  soon  after  the  onset  in  the  more  severe 
cases.  If  the  condition  is  severe  or  lasts  for  any  time  there  may  be  a 
more  persistent  leucocytosis,  and  some  myelocytes  may  appear  in  the 
peripheral  blood.  In  the  mild  forms  the  leucocyte  count  is  not  altered 
greatly.  In  many  cases  of  purpura  simplex  it  tends  to  be  rather  low. 
Blood-plates  are  nearly  always  diminished. 

Treatment. — If  it  can  be  discovered,  the  causal  condition  is  to  be 
dealt  with.  In  all  cases  it  is  important  to  keep  the  patient  at  rest  in 
bed.  In  the  cases  of  unknown  origin  anti-rheumatic  remedies  may 
be  tried,  but  are  not  as  a  rule  particularly  successful.  In  mild  purpura 
in  children  arsenic  sometimes  appears  to  do  good.  Oil  of  turpentine  has 
a  special  reputation  in  this  condition.  Calcium  salts  do  no  good.  In 
cases  where  there  seems  to  be  a  diminished  coagulability  of  the  blood 
the  administration  of  serum,  as  in  haemophilia,  might  be  worth  a  trial. 
Adrenalin  has  been  successful  in  several  instances.  The  results  of 
haemorrhage  may  require  local  treatment. 

SCUEVY — SCOKBUTUS 

Definition.  —  A  disease  characterised  by  great  debility,  a  spongy 
condition  of  the  gums,  anaemia,  and  a  tendency  to  haemorrhages. 

17 


258  PUEPUEA— SCUEVY— INFANTILE   SCUKVY 

Etiology. — Sex  and  age  have  no  special  influence.  The  essential 
cause  of  the  disease  is  deprivation  of  fresh  vegetable  food,  fresh  meat, 
and  fresh  milk.  In  past  times  it  was  the  scourge  of  sailors  on  long 
voyages,  but  it  has  also  affected  armies  in  the  field,  and  epidemics  have 
occurred  in  prisons  and  even  hospitals.  In  parts  of  Eussia  scurvy  is 
endemic  and  occasionally  becomes  epidemic. 

Sporadic  cases  are  occasionally  seen,  but  in  these  it  is  easy  to  obtain 
a  history  of  an  improper  dietary.  Such  cases  occur  most  often  among 
the  poor  of  large  towns,  especially  in  persons  who  live  alone,  and  who 
from  poverty  or  carelessness  do  not  take  a  sufficiently  varied  diet.  Old 
women  living  practically  entirely  on  tea  and  bread  and  butter  fall  easy 
victims.  Cold,  damp,  depressing  surroundings  and  overcrowding  are 
important  accessory  factors. 

Pathology. — The  morbid  changes  are  usually  well  marked,  but  they 
are  not  specific.  They  are  chiefly  the  effects  of  haemorrhage  into  the 
skin,  muscles,  connective  tissues,  and  internal  organs.  The  gums  show 
swelling  and  sometimes  ulceration.  There  may  be  ulcers  in  the  ileum 
and  colon.  The  spleen  is  enlarged  and  soft.  There  are  degenerative 
■changes  in  the  heart,  liver,  and  kidneys. 

The  intimate  nature  of  the  disease  is  not  yet  understood.  The 
symptoms  have  been  ascribed  to  the  lack  of  potassium  salts.  Another 
view  is  that  they  are  due  to  the  absence  of  salts  of  the  organic  acids, 
citrates,  tartrates,  and  malates,  leading  to  a  diminished  alkalinity  of  the 
blood.  It  is  possible  that  in  the  absence  of  these  substances  acids 
derived  from  protein  food-stuffs  are  not  adequately  neutralised,  since 
prolonged  starvation  in  itself  does  not  necessarily  cause  scurvy.  A 
different  view  of  the  disease  is  that  it  is  due  to  a  micro-organism,  although 
no  definite  germ  has  been  determined.  In  Eussia  the  disease  is  very 
generally  regarded  as  an  infection. 

Symptoms. — The  disease  begins  insidiously.  The  patient  suffers 
from  weakness  and  indefinite  pains,  and  there  is  increasing  pallor.  In 
about  a  week  petechial  spots  make  their  appearance,  generally  on  the 
legs,  and  always  starting  round  the  hair  follicles.  Larger  haemorrhages 
may  occur  and  may  cause  swellings.  There  are  often  hard  swellings  in 
connection  with  the  muscles  owing  to  haemorrhages  between  their  fibres ; 
these  are  most  common  in  the  calves.  The  gums  become  swollen,  spongy, 
and  may  ulcerate  and  bleed  readily.  This  change  is  only  seen  where 
teeth  are  present,  and  there  may  be  portions  of  comparatively  healthy 


PURPURA— SCUEVY— INFANTILE   SCURVY  259 

gum  at  parts  where  teeth  are  absent.  The  teeth  often  fall  out.  The 
breath  is  very  foetid.  The  appetite  is  impaired  apart  from  the  great  dis- 
comfort in  eating.  The  tongue  is  swollen,  red,  but  not  as  a  rule  much 
furred.  The  salivary  glands  may  be  enlarged.  Constipation  is  the 
rule ;  diarrhoea  rarely  occurs.  Palpitation,  feebleness,  and  irregularity 
of  the  heart  are  common ;  haemic  basal  murmurs  are  usually  present. 
Effusions  into  the  serous  sacs  are  not  uncommon.  The  urine  is  often 
albuminous.  Specific  gravity  is  high.  Phosphates  are  increased. 
Headache,  mental  depression  and  delirium  may  occur.  Convulsions 
and  hemiplegia  have  been  described.  Curious  ocular  symptoms  some- 
times occur.  One  of  the  most  common  is  "night-blindness"  (nyctal- 
opia), patients  being  unable  to  see  as  soon  as  dusk  begins  ;  in  other  cases 
vision  is  not  so  good  in  daylight  (hemeralopia). 

Haemorrhages  may  occur  from  any  of  the  mucous  membranes. 
Meningeal  haemorrhage  sometimes  occurs.  Subperiosteal  haemor- 
rhages, which  may  cause  sloughing  sores,  and  actual  necrosis  of  bone 
are  not  uncommon.  Old  wounds  may  break  down,  and  separation  of 
the  cartilages  from  the  sternum  and  disintegration  of  callus  in  a  recently 
repaired  fracture  have  been  described.  Arthritic  symptoms  are  some- 
times severe.  Fever  is  usually  absent  unless  there  be  inflammatory 
complications. 

The  Blood  Changes. — The  blood  changes  are  not  characteristic; 
they  are  those  of  a  secondary  anaemia,  of  varying  degree  of  severity. 
In  the  severer  cases  normoblasts  and  even  megaloblasts  may  be  seen. 
The  leucocytes,  owing  to  the  haemorrhages,  are  generally  found  to  be 
increased,  but  in  the  absence  of  recent  haemorrhage  or  inflammation 
they  are  diminished.     Blood-plates  are  diminished. 

Course. — If  the  unfavourable  conditions  which  induce  the  condition 
persist  the  outlook  is  very  grave.  Heart  failure,  sudden  syncope,  or 
exhaustion  is  a  common  termination.  Pneumonia  sometimes  super- 
venes, and  is  ill-borne.  Haemorrhage  is  seldom  serious.  Unless  the 
disease  is  very  advanced  it  yields  readily  to  treatment.  Effusions,  even 
when  blood-stained,  rapidly  clear  up,  and  other  symptoms  quickly  dis- 
appear. 

Treatment. — Prophylaxis. — Under  Board  of  Trade  regulations  ships 
must  carry  an  adequate  supply  of  lime  juice  and  other  antiscorbutics, 
so  that  scurvy  among  sailors  is  now  very  rare. 


260  PUEPUEA— SCUEVY— INFANTILE   SCUEYY 

Of-  the  Disease. — The  danger  of  sudden  syncope  must  be  guarded 
against  by  keeping  the  patient  in  bed  for  at  least  a  week.  Abundance 
of  fresh  vegetables  and  fruit  speedily  cures  any  case  of  moderate 
severity.  In  the  more  severe  cases  with  gastric  derangement,  fresh 
milk  and  scrapings  of  meat  may  be  given,  with  the  addition  of  tea- 
spoonful  doses  of  lemon  or  orange  juice.  As  the  patient  improves  the 
diet  should  be  more  liberal,  and  plenty  of  green  vegetable  food  and  fruit 
should  be  insisted  upon.  The  gums  may  be  treated  by  the  application 
of  a  solution  of  nitrate  of  silver  or  carbolic  acid  and  the  frequent  use  of 
antiseptic  and  astringent  mouth  washes.  Other  symptoms  must  be 
treated  on  general  lines. 

Infantile  Scuevy — Baklow's  Disease 

Infantile  scurvy  arises  from  improper  feeding.  Proprietary  foods, 
condensed  milk,  and  even  boiled  milk  appear  to  lack  some  antiscorbutic 
principle,  so  that  children  fed  exclusively  on  these  substances  are  liable 
to  the  disease.     The  essential  lesion  is  subperiosteal  haemorrhage. 

Symptoms. — The  affected  child  begins  to  show  indications  of  pain 
whenever  it  is  moved.  This  pain  is  at  first  limited  to  the  lower  limbs, 
especially  to  the  tibiae,  but  in  more  severe  cases  the  upper  limbs  are  also 
affected.  There  is  thickening  around  the  shafts  of  the  bones.  There  is 
often  a  certain  degree  of  symmetry  in  the  distribution  of  the  lesions. 
There  may  be  thickenings  in  connection  with  the  scapulae,  and  weakness 
of  the  back  may  be  a  noticeable  feature.  Crepitus  between  the  shaft 
and  epiphysis  of  the  long  bones  can  sometimes  be  elicited.  Sometimes 
the  sternum  and  a  portion  of  the  attached  ribs  may  sink  back  as  if  they 
had  been  subjected  to  violence.  There  may  be  thickenings  in  connection 
with  the  bones  of  the  skull  and  face.  Proptosis  may  suddenly  develop, 
with  fulness  and  ecchymosis  of  the  upper  eyelid.  The  temperature  is 
irregular.     If  teeth  have  appeared  the  gums  may  be  spongy. 

The  Blood  Changes. — There  is  always  severe  anaemia.  A  reduction 
of  red  cells  below  one  million  has  been  noted.  The  haemoglobin  shows 
a  reduction  to  a  rather  greater  extent  than  the  red  corpuscles.  Nucleated 
red  cells  are  not  uncommon.  The  leucocyte  count  is  usually  increased, 
but  the  special  blood-picture  of  young  children  must  be  borne  in  mind 
in  interpreting  the  results  of  examination.     Blood-plates  are  diminished. 

Treatment. — Prophylaxis  is  important.     Milk  should  not  be  steril- 


PUKPUEA— SCUEVY— INFANTILE   SCURVY  261 

ised  by  boiling  unless  some  fresh  meat  extract  or  fruit  juice  forms  part 
of  the  dietary,  and  children  should  not  be  fed  exclusively  or  in  large 
measure  on  proprietary  foods.  The  disease  is  readily  amenable  to 
treatment.  The  diet  should  consist  mainly  of  fresh  cow's  milk.  A 
little  fresh  meat  juice  may  be  given  with  a  small  quantity  of  mashed 
potato.  Small  quantities  of  orange,  grape,  or  sweetened  lemon  juice 
may  be  administered  several  times  daily.  The  anaemia  may  require 
the  usual  treatment,  and  the  affected  limbs  should  be  kept  at  rest  by 
bandages  and  cotton-wool  and  suitable  appliances. 


CHAPTEE  XXVI 

PAEOXYSMAL  ELEMOGLOBINUKIA 

A  disease  characterised  by  the  occasional  passage  of  blood  pigment  in 
the  urine. 

Etiology. — The  condition  is  more  frequent  in  males  than  females, 
and  usually  affects  young  adults.  A  history  of  malaria  has  been 
obtained  in  some  cases.  More  frequently  there  is  a  history  of  syphilis. 
There  is  a  certain  association  with  Eaynaud's  disease,  especially  in  the 
milder  forms  of  that  condition.  The  attacks  are  usually  determined  by 
a  chill,  sometimes  by  active  exercise.  In  predisposed  persons  washing 
the  hands  in  cold  water  may  bring  on  an  attack. 

Pathology. — The  condition  is  generally  believed  to  be  due  to  a  toxin 
in  the  blood.  According  to  Donath  and  Landsteiner  and  to  Eason  the 
toxin  acts  as  an  intermediary  body  or  amboceptor.  It  cannot  by  itself 
produce  solution  of  red  corpuscles.  For  this  the  addition  of  a  thermo- 
labile  complement  is  required.  The  intermediary  body  anchors  itself  to 
the  red  blood  corpuscles  when  they  are  exposed  to  a  temperature  lower 
than  that  of  the  body.  In  vitro  the  union  takes  place  at  0°  0.  or  at  room 
temperature.  The  further  combination  of  complement  with  the  con- 
joined corpuscles  and  intermediary  body  does  not  take  place  at  0°  C.  but 
does  so  at  room  temperature,  and  haemolysis  results.  In  vivo,  atmo- 
spheric cold  and  stasis  of  the  peripheral  circulation  probably  cause  a 
reduction  of  temperature  sufficient  to  permit  of  the  union  of  inter- 
mediary body  and  red  corpuscles.  (This  probably  accounts  for  the 
connection  with  Eaynaud's  disease.)  The  further  union  of  complement 
probably  occurs  most  rapidly  when  the  blood  returns  to  the  central 
organs.  Eason  holds  that  the  serum  at  all  times  contains  enough 
potential  toxin  to  cause  a  paroxysm,  but  the  activity  of  the  toxin  is 
manifest  or  in  abeyance  according  to  the  condition  of  the  temperature. 

Later  observations  indicate  that  the  reaction  may  not  be  so  simple, 
and  that  the  condition  of  the  serum  is  not  in  all  cases  the  same. 

A.  and  0.  Hymans  van  den  Bergh  found  that  no  lysis  followed  the 

262 


PAEOXYSMAL  ILEMOGLOBINUKIA  263 

Donath-Landsteiner  sequence  of  cooling  and  then  heating  in  three  cases. 
They  showed  that  the  cooling  of  blood  containing  the  normal  amount  of 
Co2  did  not  lead  to  lysis  on  subsequent  rise  of  temperature,  but  that  if 
blood  was  kept  for  two  hours  in  contact  with  C02  and  slightly  cooled,  a 
marked  haemolysis  occurred  when  the  temperature  rose.  They  consider 
that  the  hemolysin  is  composed  of  two  substances,  one  absorbed  by  the 
red  corpuscles,  the  other  retained  by  the  serum.  Haemolysis  occurs 
when  both  act  on  the  blood  corpuscles.  The  temperature  must  be  over 
0°  C.  and  under  37°  C. 

Mayer  and  Emmerich  made  the  interesting  observation  that  an 
attack  precipitated  by  a  cold  foot-bath  was  ushered  in  by  a  rigor  and 
that  there  was  a  great  increase  of  blood-pressure,  obviously  due  to  a 
constriction  of  peripheral  vessels.  They  also  record  an  important 
observation  regarding  the  source  of  complement.  No  free  complement 
was  found  in  the  case  of  a  patient  after  a  spontaneous  attack.  It  was 
found  that  complement  could  be  produced  locally  by  ligaturing  one 
finger  and  immersing  it  in  ice-water.  No  complement  was  yielded  by 
the  other  fingers. 

Another  view  of  the  condition  is  that  there  is  no  haemoglobinaemia,, 
and  that  the  haemolysis  is  effected  in  the  kidney  and  the  dissolved 
haemoglobin  is  directly  excreted.  A  recent  exponent  of  this  view 
is  Scheidemantel,1  who  failed  to  obtain  haemolysis  by  the  Donath- 
Landsteiner  procedure  and  could  never  find  haemoglobinaemia.  Achard 
and  Feuillie  2  afford  experimental  support  to  this  view.  By  the  injection 
of  muscle  extracts  they  obtained  haemoglobinuria  without  haemoglobin- 
aemia. There  was  a  considerable  number  of  white  cells  in  the  urine. 
There  is  general  agreement  that  the  white  cells  play  no  active  part 
in  the  production  of  the  condition,  but  Meyer  and  Emmerich  have 
found  that  the  serum  of  "  heemoglobinurikers  "  has  an  opsonic  effect 
in  increasing  the  number  of  healthy  red  corpuscles  taken  up  by  large 
lymphocytes. 

Symptoms. — The  attacks  may  be  preceded  by  rigors  and  pyrexia ; 
in  other  cases  the  haemoglobinuria  comes  on  without  warning  after  a 
chill  or  after  exertion.  The  temperature  in  these  cases  may  be  sub- 
normal. An  attack  can  often  be  determined  by  a  cold  foot-bath  or 
general  immersion.  Vomiting  and  diarrhoea  may  be  initial  symptoms. 
The  haemoglobinuria  may  last  for  two  days  but  very  frequently  only 

1  Miinch.  med.  Wochensclir.,  1909. 

2  Soc.  de  Biologie,  1909. 


264  PAROXYSMAL   HEMOGLOBINURIA 

lasts  for  a  few  hours.  In  some  cases  there  may  be  a  succession  of 
paroxysms  in  the  course  of  a  day,  the  urine  being  clear  between  times. 
Jaundice  and  pain  in  the  back  sometimes  occur.  The  urine  may  be 
merely  smoky  in  colour  or  may  be  almost  black ;  it  gives  the  usual 
tests  and  spectrum  of  oxyhemoglobin.  Total  nitrogen  is  diminished. 
Phosphorus  and  normal  urinary  pigments  are  decreased.  In  from  ten 
to  twelve  hours  after  an  attack  urobilinuria  is  usually  found.  "  Albumin- 
uria "  often  precedes  an  attack,  and  is  occasionally  to  be  found  after  the 
haemoglobin  has  disappeared.  This  may  be  explained  by  so  slight  a  degree 
of  haemolysis  that  the  spleen  and  liver  are  able  to  deal  with  the  pigment 
and  only  the  globulin  is  excreted.  There  is  often  a  deposit  of  hyaline 
or  granular  (pigment)  casts  and  half-laked  blood  corpuscles.  A  few 
white  cells  are  often  present.  No  abnormal  deposit  is  to  be  found  in 
some  cases. 

The  Blood  Changes. — The  paroxysms  may  bring  about  a  drop  in 
the  red  cell  count  of  over  one  million.  During  the  attack  the  colour 
index  is  high  owing  to  the  haemoglobinsemia.  There  is  a  polymorph 
leucocytosis.  The  day  after  the  attack  there  is  sometimes  an  increase 
in  the  number  of  eosinophils.  During  the  intervals  there  is  usually  a 
leucopenia,  and  the  percentage  of  small  lymphocytes  may  be  as  high  as 
thirty-five.     In  severe  cases  grave  secondary  anaemia  may  result. 

Prognosis. — ■  Attacks  are  likely  to  recur,  but  the  disease  is  not  usually 
attended  with  danger  to  life,  though  we  have  known  fatal  cases. 

Treatment. — Rest  and  warmth  are  essential.  If  a  patient  in  spite 
of  precautions  takes  repeated  attacks,  he  should  be  recommended  to  live 
for  some  time  in  a  warm  climate.  Arsenic  has  been  recommended,  and 
where  there  is  a  syphilitic  history  antisyphilitic  remedies  may  be  tried. 
Any  drugs  having  a  hemolytic  action,  such  as  chlorate  of  potash  and 
quinine,  should  be  avoided,  as  we  have  seen  them  cause  attacks  in  the 
subjects  of  this  condition.  During  an  attack  warmth  and  hot  drinks 
are  indicated.     Amyl  nitrate  has  been  said  to  cut  short  the  attacks. 


CHAPTER  XXVII 

BLOOD   DISEASES   IN   INFANCY  AND   CHILDHOOD 

For  some  considerable  time  after  birth  the  marrow  in  the  shafts  of  the 
long  bones  remains  red ;  there  is  therefore  comparatively  little  power 
of  compensation  or  restoration  without,  at  least,  considerable  disturb- 
ance of  those  blood-cells  which  are  concerned  in  the  reproduction  of  their 
species.  It  therefore  follows  that  hemorrhage  is  ill  borne  in  children, 
and  that  any  demand  for  an  increase  of  blood  is  met  by  a  response 
which  involves  the  output  of  nucleated  red  cells  into  the  circulation. 
These  are  in  the  first  place  normoblasts,  but  megaloblasts  are  not 
uncommonly  found,  and  in  rarer  conditions  nucleated  red  cells  with 
little  or  no  ripe  hemoglobin. 

The  same  serious  significance  is  therefore  not  to  be  attached  to 
these  appearances  as  to  the  corresponding  blood- picture  in  the  case 
of  adults. 

The  white  cells  are  more  responsive  to  stimuli  than  in  adults.  A 
much  larger  leucocytosis  is  to  be  expected  in  the  case  of  infections,  etc., 
than  would  be  likely  to  occur  in  the  corresponding  conditions  in  adults. 
Due  regard  must  be  paid  to  the  leucocyte  formula  in  health.  The 
normal  lymphocyte  percentage  is  high  in  children,  and  this  tends  to 
be  exaggerated  in  disease  (Chap.  X.). 

Pernicious  Anaemia  and  Leucooytilemia 

Pernicious  anemia  occurs  in  infancy  and  childhood  with  very  great 
rarity  (see  p.  114). 

Myelocythemia  (granular-cell  leukemia)  is  also  very  rare.1 

1  Gases  of  Myelocythcemia  in  Infancy. — 1-6.  Hutchison,  Lancet,  1904  (could  find 
only  five  authentic  cases,  and  adds  a  sixth).  7.  Ginsburg,  Inaug.  Diss.,  Zurich,  1905. 
8.  Zyberlast,  These  de  Geneve,  1906-7.  9.  Falconer,  Lancet,  1906.  10.  Ziegler  and 
Jockmann,  LJeutsch.  med.  Wochenschr.,  1907.  11.  Benjamin,  Munch.  Gesellsch.  f. 
Kinderheilk,  1908.  12.  Abt,  Arch.  Pediatrics,  1908.  13.  Leschen  and  Cleland, 
Austral.  Med.  Congress,  Melbourne,  1908  (congenital  case).  14.  Babonneix  and  Tixier, 
Archiv  de  med.  des  enfants,  1909.  15.  Dallas,  ibid.,  1910.  16.  Karsner,  Pennsylvania 
Med.  Bulletin,  1910.  17.  Whipinan,  Proc.  Royal  Soc.  of  Med.  (section,  Children's 
Diseases),  1911.      18-20.  Sternberg,   Wien.  klin.   Wochenschr.,  1911    (three   cases   in 

205 


266     BLOOD  DISEASES   IN   INFANCY  AND   CHILDHOOD 

Lymphatic  leukaemia  is  comparatively  common.  All  of  these 
diseases  have  the  same  features  as  in  adults,  but  symptoms  tend  to 
be  more  acute. 

Secondary  Anaemia 

Secondary  anaemia  is  common  in  children  as  the  result  of  de- 
ficiency in  the  iron  or  protein  content  of  the  food,  rickets,  diarrhoea, 
chronic  gastro-intestinal  catarrh,  and  acute  or  chronic  affections. 
There  is  a  diminution  in  the  number  of  red  corpuscles  and  a  pro- 
portionately greater  diminution  in  the  percentage  of  haemoglobin. 
Poikilocytosis  is  present,  but  is  generally  not  so  marked  a  feature  as 
anisocytosis.  Normoblasts  appear  in  the  peripheral  circulation,  and 
some  of  these  show  abnormalities  of  type.  In  the  severer  cases  there 
are  megaloblasts.  There  is  polychromasia  and  punctate  basophilia. 
Leucocytosis  is  the  rule.  In  the  more  moderate  instances  the  poly- 
morphs are  specially  increased ;  in  the  more  severe  cases  there  is  also 
an  increase  of  lymphocytes.  The  spleen  is  very  apt  to  be  enlarged 
in  any  case  in  which  the  anaemia  is  severe. 

Splenic  Anemia  of  Infants 

Much  confusion  has  arisen  in  connection  with  this  condition,  in 
part  due  to  the  high-sounding  title,  anaemia  pseudoleukaemica  infantum, 
applied  to  it  by  von  Jaksch.  It  is  open  to  question  whether  the  con- 
dition is  anything  more  than  a  severe  type  of  secondary  anaemia 
occurring  in  children,  but  since  the  splenic  enlargement  is  a  constant 
feature  in  splenic  anaemia  of  infants,  and  is  not  a  necessary  feature  in 
secondary  anaemia,  it  may  be  conceded  that  the  name  is  at  least  a  useful 
one  to  distinguish  a  definite  clinical  condition. 

Etiology. — The  affection  is  found  in  children  between  the  ages  of 
six  months  and  two  years.  There  is  a  record  of  one  case  at  the  age 
of  three  and  a  half  years.  According  to  Hutchison,  Jews  and  twin 
children  have  a  special  liability.  The  most  commonly  associated  con- 
dition is  rickets,  but  the  disease  affects  only  a  small  proportion  of 
rickety  children.     Syphilis  is  another  common  antecedent. 

association  with  acute  febrile  diseases).  21.  Goodall,  Edinburgh  Med.  Journ.,  1912. 
22.  Pollmann,  Munch,  vied.  Wochenschr.,  1898  (records  a  case  which  he  regards  as 
congenital).  Cassel,  Berl.  klin.  Wochenschr.,  1898,  and  Riviere,  Trans.  Royal  Med.  and 
Chirurg.  Soc,  1903,  give  references  to  cases  which  Hutchison  regarded  as  non- 
authentic. 


BLOOD   DISEASES  IN   INFANCY  AND    CHILDHOOD     267 

Pathology. — The  spleen  is  enlarged,  there  is  some  overgrowth  of 
fibrous  tissue,  and  the  Malpighian  bodies  are  indistinct.  There  is 
chronic  venous  congestion,  and  excess  of  leucocytes  and  nucleated  red 
cells  in  the  sinuses.  The  bone-marrow  is  red  and  unusually  active. 
A  fair  amount  of  megaloblastic  proliferation  may  be  made  out.  The 
aneemia  is  due  to  a  toxin  acting  on  the  blood  and  bone-marrow,  and 
the  spleen  enlarges  to  deal  with  the  effete  red  cells  and  the  excess 
of  leucocytes. 

Symptoms. — Onset  is  gradual.  Attention  is  first  attracted  to  the 
condition  either  by  general  ill -health,  pallor,  or  signs  of  some  concomi- 
tant such  as  rickets.  The  children  are  usually  apathetic  and  listless. 
The  temperature  may  be  irregular.  There  is  always  some  wasting, 
and  there  may  be  great  emaciation.  Vomiting  and  diarrhoea  sometimes 
occur.  There  may  be  heemic  cardiac  murmurs,  and  a  venous  bruit 
can  be  heard  in  the  neck.  The  abdomen  is  prominent.  Sometimes 
there  is  a  little  ascites.  The  spleen  is  greatly  enlarged  and  may 
extend  across  to  the  middle  line.  The  liver  is  enlarged,  and  in  some 
instances  its  lower  border  is  as  low  as  the  umbilicus.  Lymphatic 
glands  are  not  enlarged.  There  is  marked  pallor.  Sometimes  the 
skin  has  a  peculiar  waxy  appearance  and  may  be  pale  yellow  in  colour. 
Eowler1  has  noted  a  slight  petechial  eruption  over  the  abdomen  in 
fatal  cases. 

Blood  Changes. — In  an  extreme  case  the  red  cells  may  be  reduced 
to  a  million  and  a  half  per  cubic  millimetre.  Heenioglobin  is  reduced 
and  the  colour  index  is  always  low.  There  is  great  variation  in  the 
size  of  the  cells,  and  this  is  a  more  striking  feature  than  poikilocytosis. 
Polychromasia  is  a  marked  feature.  The  number  of  nucleated  cells 
may  be  remarkable;  over  2000  per  c.mm.  has  been  noted.  Megalo- 
blasts  may  be  very  numerous.  Even  more  primitive  forms  and  red 
cells  with  mitotic  figures  and  cells  with  fragmented  nuclei  are  not 
uncommon.  The  number  of  nucleated  red  cells  has  no  relation  to  the 
severity  of  the  disease. 

Leucocytes. — In  the  great  majority  of  cases  the  count  is  greatly 
increased  and  may  reach  60,000  per  c.mm.  A  striking  feature  is  the 
large  number  of  "  transitional "  cells.  Fowler's  differential  counts  were 
as  follows : — 

Lymphocytes,  34  to  76 ;  average,  50  per  cent. 
1  International  Clinics,  1901. 


268    BLOOD   DISEASES   IN  INFANCY  AND   CHILDHOOD 

Transitional  cells,  1  to  24;  average,  12  per  cent. 
Polymorphs,  20  to  43 ;  average,  36  per  cent. 
Eosinophils,  0  to  7 ;  average,  1J  per  cent. 

Myelocytes  may  be  found  in  almost  every  case  in  which  there  is 
a  leucocytosis. 

Diagnosis. — In  the  majority  of  cases  there  is  no  special  difficulty. 
The  age,  the  enlarged  spleen,  the  anaemia,  with  numerous  nucleated 
red  cells  and  leucocytosis,  are  the  diagnostic  features. 

Prognosis. — The  majority  of  cases  do  well.  Death  sometimes  takes 
place  from  asthenia  or  from  an  intercurrent  affection.  The  splenic 
tumour  may  disappear  in  from  six  months  to  a  year,  and  the  ansemia 
is  often  recovered  from  sooner.  Unfavourable  signs  are  marked  signs 
of  rickets  or  other  complication ;  a  marked  diminution  of  red  cells, 
and  of  their  colour  index ;  a  high  leucocyte  count,  especially  associated 
with  a  high  percentage  of  transitional  cells ;  numerous  myelocytes ; 
petechial  haemorrhages.  No  prognostic  significance  can  be  attached 
to  the  size  of  the  spleen,  to  the  number  of  erythroblasts,  the  per- 
centage of  lymphocytes,  or  the  presence  of  a  few  myelocytes.  Cases 
which  begin  to  show  improvement  generally  go  on  to  complete  recovery. 
Cowan  has  reported  two  cases  in  which  there  seemed  to  be  a  transition 
from  this  condition  to  Banti's  disease. 

Treatment. — The  chief  indication  is  the  treatment  of  the  concomi- 
tant or  causal  condition.  Arsenic  seems  to  be  of  definite  service,  and 
iron  is  not  of  much  use.  X-rays  are  of  no  service,  and  seem  even  to  be 
dangerous.  In  two  cases  reported  to  us  their  use  seemed  to  hasten 
a  fatal  issue. 

In  the  present  state  of  knowledge  splenectomy  cannot  be  recom- 
mended. 


CHAPTEE  XXVIII 

CONGENITAL  FAMILY   CHOL^EMIA 
(ACHOLURIC  JAUNDICE) 

A  congenital  disease  characterised  by  icterus,  anaemia,  and  enlargement 
of  the  spleen. 

Etiology. — In  the  majority  of  cases  the  disease  is  a  hereditary  or 
family  affection,  but  there  are  exceptions.  The  following  types 
occur : — 

1.  Hereditary  and  familial.  Cases  have  been  reported  extending 
over  four  generations  and  affecting  several  members  of  a  family  in 
each  generation.  Males  and  females  are  affected  equally,  but  in  some 
of  the  genealogies  only  one  or  other  sex  has  been  affected  throughout. 
No  instance  of  an  unaffected  member  of  a  family  transmitting  the 
disease  has  been  reported. 

2.  Family  cases  without  history  of  hereditary  transmission. 

3.  Isolated  cases  occuring  at  birth  or  in  infancy. 

4.  Cases  in  which  symptoms  do  not  appear  till  early  adolescence 
or  adult  life.1 

Pathology. — Only  a  few  post-mortem  reports  appear  to  have  been 
published.  The  liver  shows  no  special  change.  Eatty  degeneration 
has  been  noted  in  one  case.  There  is  no  cholangitis  unless  gall-stones 
have  been  present.  The  spleen  was  enlarged  in  all  recorded  cases,  and 
there  was  perisplenitis.  Some  fibrosis  has  been  noted,  but  the  chief 
change  is  simple  engorgement  and  pigmentation  mainly  in  the  endo- 
thelial cells.  The  kidneys  may  show  pigmentation  and  slight  inter- 
stitial change.  The  bone-marrow  in  one  case  was  red  throughout  the 
whole  length  of  the  femur  and  in  a  condition  of  great  activity.  The 
disease  is  probably  due  to  a  diminished  resistance  of  the  red  cells, 
which   may  be   accounted   for  by   the   presence   in   the   plasma   of  a 

1  There  is  reason  to  suppose  that  a  distinction  should  be  drawn  between  the 
"congenital"  or  "family"  cases  and  the  acquired  form.  Aschenheim  {Folia  Hcema- 
tologica,  xi.  Teil,  1911,  1)  discusses  a  case  in  point  by  the  name  of  "  Toxic-hsemo- 
lytic  Icterus  with  Splenomegaly." 

269 


270  CONGENITAL  FAMILY   CHOL^MIA 

hemolytic  toxin  of  unknown  origin,  but  it  is  possible  that  in  some 
cases  at  least  the  function  of  the  spleen  may  be  so  exaggerated  that  it 
breaks  up  corpuscles  of  normal  fragility.  The  jaundice  is  due  to 
over-production  of  bile  pigments. 

Symptoms. — A  feature  of  the  disease  is  its  comparatively  slight 
effect  on  the  general  health.  Advice  may  be  sought  on  account  of  the 
coloration  rather  than  because  of  any  special  disability.  Jaundice 
is  an  important  symptom,  but  the  diagnosis  might  be  possible  in  its 
absence  in  the  event  of  a  second  case  in  one  family.  It  is  very  rarely 
altogether  absent,  but  its  intensity  varies  very  greatly  from  time  to 
time.  It  seldom  reaches  the  degree  seen  in  cases  of  obstructive  jaundice, 
but  the  conjunctivae  are  usually  definitely  coloured  and  bile  pigment 
can  usually  be  demonstrated  in  the  blood  serum.  Patients  may  com- 
plain of  impaired  general  health  during  the  attacks  of  increased  icterus. 
The  stools  are  well  coloured,  and  there  is  no  less  of  fat  or  alteration 
in  the  proportions  of  fat,  fatty  acids,  and  soaps.  In  the  case  recorded 
by  Mackintosh,  Falconer,  and  Anderson  the  stools  were  always  more 
deeply  coloured  with  bile  on  the  occasions  on  which  their  patient 
became  more  deeply  jaundiced.  The  liver  is  either  not  at  all  or  only 
very  slightly  enlarged.  The  spleen  is  enlarged  as  an  early  symptom 
in  the  great  majority  of  cases.  The  exceptions  are  rare.  The  organ 
may  extend  to  the  level  of  the  umbilicus  or  even  lower,  and  in  time 
becomes  very  hard. 

The  majority  of  the  cases  are  acholuric,  but  in  a  few  bile  pigment 
has  been  found  in  the  urine  at  long  intervals.  Urobilin  is  generally 
present.  During  the  periods  of  increased  jaundice  there  is  generally 
a  heavy  deposit  of  urates.     Attacks  of  pyrexia  may  occur. 

Epistaxis  is  a  symptom  of  fair  frequency.  Eetinal  haemorrhages 
and  purpuric  spots  have  been  recorded  in  one  instance.  Paroxysmal 
hemoglobinuria  was  present  as  a  complication  in  one  case. 

The  Blood  Changes. — There  is  usually  a  definite  anaemia.  Eed  cell 
counts  of  about  two  millions  are  common ;  instances  have  occurred 
of  counts  below  one  million.  Poikilocytosis  is  present,  but  irregularity 
in  size  is  a  more  marked  feature.  The  average  size  of  the  red  cor- 
puscles is  much  diminished.  This  microcytosis  may  be  looked  upon 
as  one  of  the  essential  features  of  the  disease.  Polychromasia  and 
punctate  basophilia  are  fairly  common,  and  the  proportion  of  corpuscles 
showing  reticular  substance  after  vital  staining  may  reach  8  per  cent. 


CONGENITAL  FAMILY   CHOL^KMIA  271 

instead  of  the  usual  one  or  two.  Nucleated  red  cells  are  to  be  found  in 
the  more  severe  stages  of  the  disease.  These  are  mainly  normoblasts, 
but  a  few  megaloblasts  may  be  found. 

In  one  recorded  case  there  were  attacks  of  cyanosis  with  increase 
of  the  jaundice,  and  during  these  attacks  the  number  of  red  cells  rose 
from  6,000,000  to  7,600,000.  The  hemoglobin  is  diminished  to  a 
greater  degree  than  the  red  cells,  so  that  the  colour  index  is  low. 

The  leucocyte  count  does  not  show  any  special  abnormality.  The 
recorded  differential  counts  vary  considerably,  but  that  is  just  what 
might  be  expected  in  a  condition  mainly  affecting  children.  Myelo- 
cytes in  small  numbers  are  generally  found.  Bile  is  always  present 
in  the  blood-serum,  but  urobilin  is  not  found,  and  haemoglobin  has  been 
found  in  only  two  cases,  and  one  of  these  was  complicated  by  paroxysmal 
hemoglobinuria.  The  resistance  of  the  blood  to  hemolytic  agents 
is  diminished  (see  page  46).  Whereas  normal  human  red  corpuscles 
do  not  undergo  hemolysis  in  salt  solutions  stronger  than  0*4  per  cent., 
the  blood  corpuscles  in  this  disease  may  be  dissolved  in  0*7  or  0*6  per 
cent,  salt  solution. 

Diagnosis. — The  conditions  which  may  resemble  this  disease  are 
as  follows  : — 

1.  Congenital  Anosmia  with  Jaundice  from  Obliteration  or  Narrow- 
ing of  the  Bile-Ducts. — In  these  cases  the  liver  is  enlarged,  the  urine 
is  definitely  bile-stained.  There  are  often  hemorrhages.  The  blood 
tends  to  be  megalocytic  instead  of  microcytic,  and  the  resistance  to 
hypotonic  salt  solution  and  other  hemolytic  agents  is  increased  rather 
than  diminished. 

2.  Hypertrophic  Cirrhosis  of  the  Liver. — This  affection  is  sometimes 
met  with  as  a  family  disease.  The  liver  is  enlarged,  there  is  jaundice 
with  bile  pigment  in  the  urine,  the  children  are  deficient  physically 
and  often  mentally.  The  blood  changes  are  those  of  somewhat  mild 
secondary  anemia. 

3.  Congenital  Syphilis. — The  presence  of  signs  of  syphilis  apart  from 
those  common  to  the  two  conditions  and  the  Wassermann  or  luetin 
reaction  would  distinguish  this  disease. 

4.  Pernicious  Anosmia. — Cases  of  pernicious  anemia  in  infants  are 
excessively  rare.  It  may  be  difficult  to  distinguish  it  from  cases  of 
acholuric  jaundice  developing  at  or  after  puberty.  Cases  of  what  seem 
to  us  clear  examples  of  pernicious  anemia  have  been  recorded  as 
acholuric  jaundice.     The  chief  diagnostic  point  must  be  the  examination 


272  CONGENITAL   FAMILY   CHOL^MIA 

of  the  blood.  The  megaloblastic  and  megalocytic  anaemia  with  high 
colour  index,  and  the  leucopenia  with  the  relative  lymphocytosis  of 
pernicious  anaemia,  contrast  strongly  with  the  typical  changes  in 
acholuric  jaundice.  It  should  not  be  forgotten  that  a  slight  degree 
of  jaundice  is  not  uncommon  in  acute  cases  of  pernicious  anaemia. 

5.  Splenic  Ancemia. — Both  the  ordinary  type  and  the  Gaucher  type 
may  be  family  diseases.  Jaundice  is  absent  in  the  ordinary  form  until 
the  stage  of  Banti's  disease  is  reached,  but  has  been  found  in  cases 
of  the  Gaucher  type.  The  blood  changes  are  comparatively  slight  in 
the  early  stages,  and  differ  from  those  of  acholuric  jaundice  throughout 
(Chap.  XVIII.). 

Prognosis. — The  disease  is  very  rarely  fatal  and  has  very  little 
tendency  to  shorten  life.  Several  female  cases  have  been  mothers  of 
large  families.  The  cases  developing  in  later  life  are  much  more 
serious  than  the  cases  with  symptoms  developed  at  birth  or  in  infancy. 
The  older  cases  as  a  rule  show  more  anaemia  and  less  jaundice  than  the 
infantile  cases. 

Treatment. — Treatment  is  seldom  called  for,  and  in  many  instances 
is  only  required  to  meet  special  symptoms.  Arsenic  appears  to  be  of 
no  use.  When  symptoms  are  distressing  or  causing  much  disability  the 
question  of  splenectomy  may  be  considered. 

A  small  number  of  cases  of  apparently  complete  recovery  after  this 
procedure  are  now  on  record,  but  the  operation  is  not  without  risk. 
Operations  for  complicating  gall-stones  appear  to  have  been  success- 
fully performed  in  two  cases.     One  case  of  cholecystectomy  was  fatal. 

Literature 

An  admirable  account  of  the  disease  and  full  references  are  given  by 
Mackintosh,  Falconer,  and  Anderson,  Edinburgh  Med.  Joum.,  March  1911. 


Congenital  Anemia  with  Obstructive  Jaundice 

A  group  of  cases  has  been  described  in  which  anaemia,  jaundice,  and 
varying  degrees  of  biliary  obstruction  have  been  the  chief  features.  Only 
a  few  cases  have  been  studied  by  modern  haematological  methods.  The 
disease  may  affect  several  members  of  one  family  in  which  the  parents 
have  been  healthy.     Single  cases  in  a  family  have  occurred.     The  liver 


CONGENITAL  FAMILY   CHOL^MIA  273 

shows  evidence  of  biliary  obstruction,  either  through  congenital  obstruc- 
tion or  obliterative  cholangitis. 

In  Buchan  and  Comrie's  cases  there  were  erythroblastic  areas  in 
the  liver ;  the  bone-marrow  was  very  active.  At  the  same  time  there 
was  evidence  of  destruction  of  blood  corpuscles  by  circulating  phago- 
cytes and  by  endothelial  cells  in  the  lymph  glands  and  spleen.  The 
iron  reaction  was  found  in  the  spleen.  The  disease  is  probably  due 
in  part  to  the  hemolytic  action  of  the  bile  and  in  part  to  the  retention 
of  toxins  which  are  normally  taken  up  and  excreted  by  the  liver. 

Symptoms. — The  symptoms  are  jaundice  at  birth  or  developing  very 
shortly  afterwards.  The  urine  is  bile-stained,  the  fasces  are  acholic. 
The  liver  and  spleen  are  enlarged.  Haemorrhages  are  common.  There 
is  profound  ansemia.  Eed  cells  number  roughly  from  1|  to  2|  millions. 
The  colour  index  tends  to  be  high.  The  average  size  of  the  corpuscles 
is  increased.  Poikilocytes  are  not  specially  numerous.  Polychromasia 
is  very  marked,  and  punctate  basophilia  is  generally  present.  Nucleated 
red  cells  are  very  common,  and  megaloblasts  often  preponderate.  In 
addition  to  megaloblasts  there  are  numerous  cells  of  a  more  primitive 
type.  Cells  with  mitotic  figures  and  pyknotic  nuclei  may  be  found. 
There  is  very  marked  leucocytosis.  The  percentages  of  the  different 
varieties  are  not  greatly  different  from  the  infant  formula  in  health. 
Myelocytes  are  present  in  fair  numbers.  Eosinophils  are  in  normal 
proportions ;  a  few  show  immature  (basophil)  granules.  Some  of  the 
large  lymphocytes  show  evidence  of  phagocytosis  of  red  cells.  The 
blood-plates  are  diminished.  The  red  cells  show  a  high  degree  of 
resistance  to  hemolytic  agents. 

Prognosis. — The  great  majority  of  cases  die  within  ten  months  of 
birth.     A  few  cases,  however,  have  recovered  completely. 

Literature 
Buchan  and  Comrie,  Journ.  of  Path,  and  Bad.,  xiii.  1909. 


18 


CHAPTEE  XXIX 

LYMPHATISM— STATUS   LYMPH ATICUS  —STATUS 
THYMICUS 

A   disease   associated   with   an   enlarged   thymus  and  hyperplasia  of 
lymphoid  tissue,  characterised  by  a  tendency  to  sudden  death. 

Etiology. — The  condition  is  found  in  children  and  more  rarely  in 
young  adults.  The  actual  cause  of  the  condition  is  altogether  obscure. 
It  has  been  suggested  that  it  is  due  to  malnutrition  in  early  childhood. 
Some  cases  have  occurred  in  epileptics,  and  rickets  is  not  uncommonly 
associated  with  it. 

Pathology. — The  principal  morbid  change  found  is  an  enlargement 
of  the  thymus.  The  change  chiefly  consists  in  a  hyperplasia  of  the 
glandular  tissue.  The  Hassall's  corpuscles  may  have  the  usual  con- 
centric structure  or  may  exhibit  the  stage  before  the  formation  of  the 
concentric  bodies,  viz.  healthy  and  broken-down  epithelial  cells  invaded 
by  polymorphonuclear  leucocytes  and  lymphocytes.  The  follicles  at 
the  base  of  the  tongue,  the  tonsils,  and  the  Peyer's  patches  and  solitary 
follicles  may  show  enormous  enlargement.  The  Malpighian  bodies  of  the 
spleen  and  varying  groups  of  lymphatic  glands  are  also  enlarged.  The 
heart  is  often  dilated,  its  muscle  is  flabby,  and  in  some  cases  a  narrowing 
of  the  aorta  has  been  described.  The  bone-marrow  is  often  red  in  the 
shafts  of  the  long  bones,  even  in  adults.  The  thyroid  has  been  enlarged 
in  a  fair  proportion  of  cases. 

The  sudden  death  which  takes  place  in  so  many  of  the  cases  is  due 
in  some  instances  to  compression  of  the  trachea  by  the  enlarged  thymus. 
This  is  especially  likely  to  occur  in  young  infants,  but  ordinarily  the 
enlargement  of  the  thymus  is  only  a  part  of  the  lymphoid  hyperplasia, 
and  the  condition  is  probably  to  be  regarded  as  one  of  chronic  toxaemia. 

Buzzard  calls  attention  to  the  similarity  between  some  of  the  cases 
and  cases  of  myasthenia  gravis.    In  the  latter  condition  there  are  collec- 

274 


LYMPHATISM  275 

tions  of  lymphocytes  in  the  organs,  tissues,  and  muscles.  The  thymus 
is  enlarged  in  over  50  per  cent,  of  cases,  and  death  often  occurs  suddenly 
from  failure  of  the  respiration  or  heart.  Again,  it  has  been  sought  to 
establish  a  connection  between  lymphatism  and  exophthalmic  goitre, 
in  which  the  thymus  is  often  enlarged.  Mair  reports  a  case  associated 
with  Zenker's  degeneration  of  the  muscles. 

Symptoms. — The  recognition  of  the  condition  during  life  is  difficult, 
and  the  diagnosis  is  very  seldom  made.  There  is  pallor.  The  tempera- 
ture is  often  subnormal.  There  may  be  evidence  of  an  enlarged  thymus 
in  the  existence  of  an  area  of  percussion  dulness  in  the  region  of  the 
manubrium  sterni,  but  this  dulness  is  often  not  well  marked.  Some- 
times the  enlarged  thymus  tends  to  push  down  the  heart  so  that  the 
upper  border  of  the  superficial  cardiac  dulness  is  lowered.  There  is 
hypertrophy  of  the  tonsils  and  the  lymphoid  tissue  about  the  mouth. 
Sundry  groups  of  lymphatic  glands,  especially  those  about  the  neck,  may 
be  enlarged.  The  tongue  is  large  as  a  whole  and  the  papillae  are 
prominent.  There  is  sometimes  a  symmetrical  enlargement  of  the 
thyroid  gland.  The  heart  sounds  are  muffled  and  faint.  The  pulse 
is  slow  and  the  blood-pressure  is  diminished. 

The  outstanding  feature  of  the  condition  is  the  remarkable  tendency 
to  sudden  death  from  apparently  trivial  or  undiscoverable  causes.  The 
occurrence  of  sudden  death  {thymus  tod)  is  generally  the  first  intima- 
tion of  the  presence  of  the  condition.  In  some  cases  there  has  been 
stridor  for  a  few  weeks.  In  other  instances  there  have  been  increasing 
attacks  of  dyspnoea,  but  usually  there  is  simply  cessation  of  respiration 
or  of  the  heart  without  warning.  The  antecedent  circumstances  have 
been  very  diverse.  Some  cases  have  been  found  dead  in  bed.  Trivial 
occurrences  such  as  a  slight  burn  or  a  hypodermic  injection  of  diphtheria 
antitoxin  or  of  cocaine  for  local  anaesthesia  have  been  followed  by  death. 
In  other  cases  the  fatal  result  has  followed  a  fright  or  emotional  con- 
dition or  bathing.  Particular  attention  has  been  attached  to  those  cases 
following  the  administration  of  a  general  anaesthetic. 

Thursfield  has  reported  a  case  in  which  death  occurred  in  his 
presence  without  apparent  cause. 

"A  boy,  aged  thirteen  months,  was  admitted  to  the  wards  with 
rickets  and  tetany.  The  last  was  very  slight ;  a  fit  was  said  to  have 
occurred  on  the  previous  day.  While  I  was  standing  at  the  side  of  the 
cot  the  child  suddenly  sat  up,  its  eyes  became  fixed,  it  ceased  to  breathe, 
became  very  slightly  blue,  then  quite  white,  and  fell  back  dead.     The 


276  LYMPHATISM 

whole  series  of  events  occupied  less  than  thirty  seconds.  There  was 
certainly  no  question  of  asphyxia ;  it  appeared  rather  as  if  both  circu- 
latory and  respiratory  centres  struck  work  simultaneously." 

Bellamy  Gardner  gives  an  admirable  account  of  an  anaesthetic  case. 
Patient  was  a  boy,  aged  thirteen.  The  anaesthetic  was  chloroform  one 
part,  and  ether  two  parts,  by  volume.  The  operation  was  for  the 
enucleation  of  deep-seated  tonsils  and  very  large  adenoids.  Anaesthesia 
was  induced  uneventfully. 

"At  this  third  sweep  of  the  curette  the  patient  made  a  very  slight 
retching  movement,  and  a  little  bluish  blood  appeared  in  the  pharynx  ; 
his  head  and  body  were  rotated  to  the  right  side  for  drainage,  and  a 
teaspoonful  of  bilious  fluid  was  ejected  from  the  right  corner  of  the 
mouth  and  he  stopped  breathing.  The  throat  was  sponged.  I  squeezed 
his  chest ;  air  escaped  and  entered  audibly.  I  looked  into  the  pharynx 
and  felt  behind  the  tongue;  there  was  no  blood  or  other  obstruction 
there.  Suddenly  a  deep  navy  blue  colouration  appeared  on  the  forehead 
and  temples,  slanting  away  towards  the  ears,  with  a  definite  border 
along  the  zygomatic  arch.  The  lips,  ears,  and  face  were  at  the  same 
time  almost  normal  in  colour.  The  corneal  reflex  now  disappeared,  and 
the  pupil,  which  had  been  about  2 \  mm.  in  diameter,  enlarged  to  4  or 
4|  mm.  From  the  moment  of  the  respiratory  paralysis  not  one  single 
natural  muscular  or  respiratory  movement  ever  took  place." 


The  Blood. — There  is  anaemia  of  a  chlorotic  type.  The  leucocyte 
count  may  be  slightly  increased.  There  is  a  moderate  lymphocytosis,, 
absolute  or  relative. 


Treatment. — Unfortunately  most  cases  are  beyond  the  reach  of  treat- 
ment before  the  diagnosis  is  made.  Should  a  case  be  recognised  during 
life  it  is  obvious  that  special  care  will  be  demanded  in  the  avoidance 
of  disturbances  which  might  lead  to  a  fatal  termination.  Since  arsenic 
does  good  in  many  forms  of  lymphoid  hyperplasia,  it  would  be  worth 
a  trial  in  this  disease.  Eachford1  has  treated  two  cases  successfully 
with  X-rays.  While  it  would  be  unwise  to  exaggerate  the  danger  of 
anaesthesia,  owing  to  the  possibility  of  lymphatism,  it  would  be  folly  to 
minimise  it.  In  cases  of  possible  operation,  where  there  is  lymphoid 
hypertrophy,  it  would  be  well  to  examine  closely  for  indications  of  the 
1  Araer.  Journ.  of  Med.  Sci.,  October  1910. 


LYMPHATISM  277 

disease,  since  the  induction  of  anaesthesia  and  the  operation  per  se  are 
fraught  with  special  risks  when  it  is  present. 

Literature 

Paltauf,  Wien.  Iclin.  Wochenschr.,  h.  1889,  877.  Gardner,  Buzzard, 
Humphry,  and  others,  Proc.  Boy.  Soc.  of  Med.  (Sect.  Anaesthetics),  1909-10. 
Thursfield,  St.  Bart.'s  Hosp.  Reports,  1903,  129.  Buxton,  Lancet,  6th  August 
1910.     Mair,  Med.  Chronicle,  January  1911. 


PART    IV 
THE   BLOOD   IN   SPECIAL  DISEASES 

CHAPTEE  XXX 

INFECTIOUS   DISEASES 

Introduction. — In  febrile  conditions  blood-counts  may  be  affected  by 
vasomotor  disturbances,  but  only  to  a  very  slight  extent.  During  the 
course  of  the  fever  there  may  be  concentration  of  the  blood  due  to 
contraction  of  vessels  and  to  loss  of  fluid.  After  a  fever  there  is  often 
dilatation  of  vessels  and  a  corresponding  drop  in  the  blood-counts.  In 
most  fevers  there  is  a  considerable  leucocytosis.  (The  exceptions  are 
stated  on  p.  76.)  The  extent  of  the  leucocytosis  depends  on  the 
nature  of  the  infection,  its  severity,  and  the  powers  of  resistance  of  the 
organism.  An  infection  may  be  so  slight  that  no  stimulus  is  given  to 
the  bone-marrow,  and  no  increased  number  of  leucocytes  is  sent  out, 
or  so  severe  that  the  bone-marrow  is  poisoned  before  it  can  react. 
Between  these  extremes  there  may  be  a  varying  degree  of  stimulation 
and  a  varying  amount  of  reaction.  Leucocytosis  is  not  dependent  on 
the  rise  of  temperature.  The  degree  of  fever  and  the  extent  of  the 
leucocytosis  seldom  correspond,  and  show  variations  independent  of 
each  other.  In  most  of  the  common  fevers  the  blood-plates  are 
diminished  in  number. 

Scarlet  Fever. — The  red  corpuscles  are  affected  only  in  severe  cases. 
In  these  there  may  be  a  drop  of  half  a  million.  The  white  cells  show 
very  definite  changes.  These  have  been  very  fully  studied  by  Bowie,1 
who  finds  that  practically  all  cases  show  leucocytosis,  which  begins  in 
the  incubation  period  very  shortly  after  infection,  reaches  its  maximum 
at  or  shortly  after  the  height  of  severity  of  the  disease,  and  then 
gradually  sinks  to  normal.  In  simple  uncomplicated  cases  the 
maximum  is  reached  during  the  first  week,  and  the  normal  generally 

1  Bowie,  Joum.  of  Path,  and  Bad.,  1902,  82. 

278 


INFECTIOUS   DISEASES  279 

some  time  during  the  first  three  weeks.  The  more  severe  the  case  the 
higher  and  more  persistent  is  the  leucocytosis.  A  favourable  case  in 
any  one  variety  of  the  disease  (simple,  anginose,  etc.)  has  a  higher 
leucocytosis  than  an  unfavourable  one  of  the  same  variety.  Bowie's 
highest  count  in  simple  cases  was  35,000,  in  anginose  cases  43,000. 
The  polymorphs  are  increased  relatively  and  absolutely,  and  may 
constitute  90  per  cent,  of  the  total. 

Eosinophils  are  diminished  at  the  onset  of  the  fever.  They  increase 
rapidly  in  simple  favourable  cases  till  the  height  of  the  disease  is  past. 
They  may  number  11  per  cent,  on  the  third  day.  Eosinophilia  may 
persist  after  the  total  count  has  reached  normal.  The  more  severe 
the  case  the  longer  are  the  eosinophils  subnormal  before  they  rise 
again  ;  in  fatal  cases  they  never  rise,  and  generally  disappear  altogether 
from  the  circulation.  The  behaviour  of  the  eosinophils  may  be  of 
diagnostic  value  in  mild  cases.  The  increase  of  these  cells  early  in 
the  disease  may  help  to  distinguish  it  from  cases  of  tonsillitis  and 
septic  conditions. 

Klotz  l  has  described  diminished  staining  affinities  of  the  eosinophils 
in  malignant  cases,  and  in  these  the  leucocytes  show  a  well-marked 
glycogen  reaction.  In  complications  the  leucocytes  go  through  a  cycle 
of  events  similar  in  all  respects  to  that  of  the  primary  fever. 

According  to  Tschistowitsch 2  the  blood-plates  may  be  normal  or 
diminished  on  the  first  day  of  the  disease,  but  thereafter  show  an 
abrupt  increase.  Complications  associated  with  fever  cause  a  tem- 
porary diminution. 

Inclusion  Bodies.3 — In  1911  Dohle  described  what  he  called  "inclu- 
sion bodies  "  in  the  leucocytes  in  cases  of  scarlet  fever.  These  bodies 
are  easily  demonstrated  in  films  by  any  of  the  ordinary  basic  stains 
(carbol-methylene  blue,  carbol-thionin,  etc.)  after  fixation.  They  are 
found  in  the  protoplasm  of  polymorphonuclear  cells  only,  and  are  round, 
oval,  or  slightly  elongated  bodies  which  closely  resemble  micrococci. 
They  are  probably  products  of  degeneration  in  the  cytoplasm.  They 
are  present  in  at  least  90  per  cent,  of  cases  of  scarlet  fever  during  the 
first  four  days.  They  are  sometimes  absent  in  severe  fatal  cases. 
After  the  fourth  day  they  diminish  in  number,  but  generally  persist 
for  at  least  a  week.  The  bodies  are  also  found,  though  in  smaller 
numbers,  in  measles,  rotheln,  diphtheria,  tonsillitis,  typhus,  etc.,  and 

1  Klotz,  Journ.  of  Infect.  Diseases,  1904,  404. 

2  Folia  Hcematologica,  iv.  295. 

3  See  Granger  and  Pole,  Brit.  Journ.  of  Children's  Diseases,  January  1913,  and 
M'Ewan,  Journ.  of  Path,  and  Bad.,  1914,  456. 


280  INFECTIOUS   DISEASES 

in  most  diseases  caused  by  pyogenic  organisms.  They  are  absent  in 
cases  of  serum  rashes  and  other  toxic  eruptions,  so  that  the  fact  of 
their  presence  or  absence  may  have  slight  diagnostic  value  in  some 

cases. 

Measles. — Most  observations  indicate  that  there  may  be  a  slight 
or  more  rarely  a  marked  leucocyte  increase,  with  increased  percentage  of 
polymorphs,  during  the  incubation  stage.  During  invasion  the  number 
diminishes,  and  during  and  after  the  eruption  there  is  leucopenia 
associated  with  a  high  percentage  of  large  lymphocytes.  Eosinophils 
are  diminished,  and  do  not  return  to  normal  till  desquamation  has 
begun.  All  complications  produce  leucocytosis.  The  diagnostic  value 
of  the  leucopenia  is  very  considerable. 

Rotheln. — The  leucocyte  changes  are  similar  in  character  to  those  of 
measles,  but  are  less  marked  and  much  less  constant.  Red  corpuscles 
and  blood-plates  are  not  affected. 

Mumps. — Feiling1  found  a  slight  increase  of  white  cells  with 
lymphocytosis,  which  was  present  on  the  first  day,  and  persisted  for 
at  least  a  fortnight.  Orchitis  did  not  alter  the  blood-picture,  but  other 
observers  have  found  that  orchitis  generally  produces  a  slight  poly- 
morph leucocytosis. 

Whooping- Cough. — Churchill 2  found  lymphocytosis  in  93  per  cent, 
of  42  cases  in  the  catarrhal  stage.  Crombie3  studied  112  cases,  and 
found  that  lymphocytosis,  either  absolute  or  relative,  was  constant. 
His  average  count  in  the  catarrhal  stage  was  20,237  white  cells 
per  c.mm.,  with  66  per  cent,  of  lymphocytes.  In  whooping-cough 
the  divergence  from  the  normal  blood-picture  is  so  great  that  it  is 
seldom  necessary  to  consider  the  age  of  the  child.  A  high  leucocytosis 
at  the  outset  points  to  a  severe  and  prolonged  attack.  In  the  later 
stages  the  leucocyte  count  varies  directly  with  the  number  and  severity 
of  the  paroxysms. 

Cases  complicated  with  pneumonia  may  show  very  high  leucocyte 
counts.  Crombie  reports  the  case  of  a  child  of  twenty  months  with 
233,000  per  c.mm.,  of  which  58  per  cent,  were  lymphocytes.     Similar 

1  Lancet,  12th  July  1913,  71. 

2  Journ.  Amer.  Med.  Assoc,  1906,  1506. 

3  Edin.  Med.  Journ.,  1908,  3. 


INFECTIOUS   DISEASES  281 

cases  have  been  reported  by  other  authors.  The  lymphocyte  increase 
has  been  ascribed  to  irritation  of  the  bronchial  lymph-glands,  but  these 
could  not  possibly  supply  so  large  a  quantity,  and  as  the  polymorphs  are 
so  greatly  increased  also  in  total  number,  though  not  in  proportion,  there 
is  every  reason  to  believe  that  both  increases  are  derived  from  the  bone- 
marrow,  and  are  chemiotactic  in  origin. 

Influenza.  —  In  a  prolonged  or  severe  case  there  may  be  slight 
ansemia.  In  uncomplicated  cases  there  is  no  increase  of  white 
cells,  and  even  in  cases  with  slight  broncho-pneumonia  the  rise  may  be 
absent  or  ill-marked.  This  normal  count  is  often  of  great  value  in 
excluding  septic  processes  when  fever  is  long  continued,  but  gives  no 
help  in  the  diagnosis  from  tubercle  or  typhoid. 

Diphtheria. — Slight  ansemia  may  occur,  less  marked  if  antitoxin  be 
given  early.  Sometimes  the  blood  becomes  concentrated  at  the  height  of 
the  disease,  and  the  count  is  higher  than  normal.  The  white  cells  are 
usually  increased  in  number ;  a  common  figure  is  20,000.  In  very  mild 
and  very  severe  cases  leucocy  tosis  is  commonly  absent.  The  cells  causing 
the  increased  counts  are  the  polymorphs.  The  leucocytosis  is  practic- 
ally unaffected  by  serum  treatment,  and  it  may  persist  for  a  short  time 
after  the  disappearance  of  the  membrane.  The  glycogen  reaction  is  not 
present  unless  there  be  much  local  inflammation.  Blood-plates  show  a 
marked  and  persistent  reduction. 

Typhoid. — The  red  corpuscles  during  the  first  two  weeks  show  very 
little,  if  any,  change.  In  the  third  week  a  diminution,  which  may 
become  considerable,  begins.  Counts  falling  below  2,000,000  have 
been  recorded.  As  is  usual  in  secondary  ansemia,  the  haemoglobin  loss 
is  rather  greater  than  that  of  the  erythrocytes.  There  may  be  a 
transient  slight  initial  leucocytosis,  but  in  the  absence  of  complications 
there  is  usually  none.  Almost  at  the  outset  an  increase  of  lympho- 
cytes, especially  of  the  large  forms,  begins  at  the  expense  of  the  poly- 
morphs. This  change  becomes  progressively  more  marked,  and  in  the 
later  stages  there  is  an  actual  leucopenia,.  due  to  a  diminution  of  poly- 
morphs. This  leucopenia  may  occur  early.  We  have  repeatedly  seen 
counts  of  4000  in  the  first  week,  but  it  is  more  usual  to  have  a  practically 
normal  count  at  that  stage.  Perforation  is  usually  associated  with 
leucocytosis,  unless  the  patient  be  already  profoundly  poisoned.  Eosino- 
phils are  diminished,  and  their  disappearance  before  the  third  week  is 


282  INFECTIOUS   DISEASES 

of  unfavourable  omen.  Late  complications  with  mixed  infection  usually 
show  leucocytosis,  but  as  a  general  rule  the  polymorph  proportion  in 
these  cases  is  not  so  high  as  it  would  be  in  the  absence  of  typhoid. 
This  holds  for  such  complications  as  periostitis,  terminal  pneumonia, 
cholecystitis,  pleurisy,  and  empyema.  The  absence  of  leucocytosis  and 
the  high  percentage  of  lymphocytes  are  of  very  great  value  in  diag- 
nosis, and  in  many  cases  the  blood  examination  will  clear  up  a  diagnosis 
of  typhoid  before  the  Widal  reaction  is  available.  The  glycogen  reaction 
is  never  intense,  and  does  not  appear  before  the  end  of  the  second  week. 

Eberth's  bacillus  is  found  in  the  blood,  and  can  be  cultivated  in  the 
great  majority  of  cases  in  the  second  and  third  weeks. 

Cummins  recommends  a  solution  of  0*5  per  cent,  taurocholate  of 
soda  in  water  as  a  useful  medium  for  early  diagnosis.  Only  1*5  c.c. 
of  blood  need  be  added  to  5  c.c.  of  the  bile  water. 

The  conditions  which  are  most  often  mistaken  for  typhoid  can  in  the 
majority  of  instances  be  diagnosed  from  it  by  a  blood  examination,  if 
thorough  physical  examination  leaves  doubt  in  the  mind  of  the  attendant. 
Judging  from  the  statistics  of  fever  hospitals,  pneumonia  is  the  most 
frequent  error.  Here  the  leucocytosis  which  occurs  in  nine  cases  out  of 
ten,  at  least,  with  the  high  polymorph  percentage  and  marked  glycogen 
reaction,  should  prevent  mistake.  The  very  slight  cases  with  moderate 
or  absent  leucocytosis  are  not  likely  to  cause  error,  as  in  them  there 
is  hardly  ever  sufficient  distension  of  the  abdomen  or  sufficient  disturb- 
ance of  digestion  to  induce  the  thought  of  typhoid.  The  severe  cases 
with  leucopenia  are  most  likely  to  be  notified  as  typhoid,  for  they  may 
show  marked  abdominal  distension,  and  in  the  differential  count  the 
polymorph  percentage  may  be  as  low  as  60,  but  the  glycogen  reaction 
is  always  so  intense  that  nothing  but  a  severe  peritonitis  in  typhoid 
could  equal  it.  The  pneumonia  which  occurs  occasionally  early  in 
typhoid  does  not  in  our  experience  greatly  raise  the  leucocyte  count, 
the  polymorph  percentage  is  not  high,  and  the  glycogen  reaction,  if 
present  at  all,  is  always  slight. 

In  those  cases  of  influenza  which  show  protracted  fever  and  which 
sometimes  resemble  typhoid,  the  blood  will  not  help,  and  Widal's 
reaction,  the  diazo  test,  etc.,  must  decide  the  difficulty.  The  same 
holds  with  regard  to  acute  miliary  tuberculosis,  in  which  case  a  per- 
sistently negative  Widal,  and  the  fact  that  the  bacillus  typhosus  cannot 
be  isolated  from  the  blood,  may  sometimes  be  the  only  means  of 
distinguishing  the  two  conditions. 

Tuberculous  meningitis  gives  a  leucocytosis  with  increased  poly- 


INFECTIOUS   DISEASES  283 

morph  percentage  so  constantly  that  the  great  majority  of  doubtful 
cases  may  be  distinguished  in  this  way.  We  have,  however,  seen  cases 
with  counts  of  7000  and  8000  at  the  beginning  of  illness,  but  these 
developed  higher  counts  when  followed  up.  There  are  certain  cases 
of  typhoid,  moreover,  in  which  there  is  persistent  leucocytosis  through- 
out, with  no  discoverable  complications,  but  these  are  very  rare. 

Acute  enteritis  always  shows  a  rather  high  leucocytosis,  20,000  to 
25,000 ;  and  appendicitis,  of  the  type  likely  to  be  mistaken  for  typhoid, 
also  has  usually  both  a  leucocytosis  and  a  definite  glycogen  reaction. 

Typhus. — Eecent  observations  have  been  made  by  Love,1  Slatineano 
and  Galesesco,2  and  Lucksch.3  The  red  cells  may  be  increased  during 
the  fever,  but  anaemia  with  poikilocytosis  soon  becomes  marked.  Leuco- 
cytosis is  the  rule;  it  may  appear  before  or  with  the  eruption.  The 
leucocytosis  usually  increases  just  before  the  crisis,  and  falls  on  the 
day  following,  but  the  count  does  not  reach  normal  till  convalescence  is 
established.  The  leucocytosis  is  mainly  polymorphonuclear,  but  lympho- 
cytes are  also  increased,  and  in  the  later  stages  may  reach  percentages 
of  45  or  50.  Eosinophils  are  diminished,  and  may  be  absent  in  fatal 
cases.     Blood-plates  are  increased. 

Smallpox. — When  the  temperature  falls  a  considerable  diminution 
of  red  cells  is  found.  Nucleated  red  cells  may  be  present  in  small 
numbers,  especially  in  hemorrhagic  cases.  There  is  leucocytosis  from 
the  beginning,  but  it  is  greatest  during  the  vesicular  stage.  The 
increase  chiefly  affects  the  lymphocytes,  which  may  amount  to  60 
per  cent.  Myelocytes  of  all  kinds  may  occur,  and  pro-myelocytes 
are  not  uncommon.  The  blood-picture  is  the  same  in  all  varieties 
of  the  disease,  and  is  not  modified  by  complications.  The  changes 
persist  well  into  the  convalescent  stage. 

Varicella. — There  may  be  a  slight  polymorph  leucocytosis,  but  the 
total  count  per  cubic  millimetre  is  frequently  unaffected.  A  relative 
lymphocytosis  has  been  noted  in  the  later  stages,  but  is  not  constant. 

Vaccination. — There  may  be  a  moderate  polymorph  leucocytosis, 
beginning  on  the  third  or  fourth  clay  and  lasting  till   the   seventh 

1  Journ.  of  Path,  and  Bad.,  x.  1905. 

2  Societe  de  Biologie,  lxi.  1906,  85. 

3  Folia  Hcematologica,  iv.  1907,  520. 


284  INFECTIOUS   DISEASES 

or  eighth  day.     This  is  followed  by  leukopenia,  and  occasionally  by 
a  slight  lymphocytosis. 

Epidemic  Cerebro-Spinal  Meningitis. — Leucocytosis  is  the  rule. 
Fowler  found  counts  ranging  from  14,000  to  38,000,  and  there  was 
almost  constantly  a  positive  glycogen  reaction. 

Cholera. — Biernacki x  found  red  cell  counts  exceeding  7,000,000 
owing  to  the  concentration  of  the  blood.  The  specific  gravity  may  be 
increased  to  1072.  Leucocytosis  is  an  early  symptom,  and  is  greater 
than  mere  concentration  of  the  blood  would  account  for.  The  count 
may  reach  60,000.  The  increase  consists  of  polymorphs.  Kogers2 
found  similar  changes  with  diminution  of  eosinophils.  Eogers3  has 
also  shown  that  the  determination  of  the  specific  gravity  of  the  blood 
is  of  supreme  importance  in  cholera.  If  the  specific  gravity  is  below 
1062  the  case  is  only  a  mild  one;  the  vomiting  and  diarrhoea  have  not 
deprived  the  blood  of  more  than  one-third  of  its  plasma,  and  treatment 
with  saline  infusion  is  not  required.  If  the  specific  gravity  is  between 
1062  and  1066,  as  much  as  one-half  of  the  fluid  may  have  been  lost 
from  the  blood,  the  case  is  a  severe  one,  and  80  ounces  of  saline  solution 
should  be  administered.  In  severe  cases  as  much  as  two-thirds  of  the 
fluid  may  be  lost  from  the  blood,  and  its  specific  gravity  is  therefore 
raised  to  from  1067  to  1076.  In  such  cases  120  ounces  of  saline  must 
be  at  once  administered. 

Dysentery. — The  red  cells  are  not  affected  in  early  cases,  but  in 
chronic  cases  secondary  anasmia  develops.  In  the  great  majority  of 
cases  there  is  a  polymorph  leucocytosis.  Eogers4  found  that  counts 
above  15,000  per  c.mm.  were  very  rare  in  bacillary  dysentery,  but  that 
much  higher  figures  were  usually  found  in  amoebic  cases.  A  leucocy- 
tosis of  over  20,000  occurring  in  dysentery  is  an  almost  certain  indica- 
tion of  its  amoebic  nature,  and  the  degree  of  leucocytosis  is  proportionate 
to  the  severity  of  the  condition.  Eosinophilia  has  been  recorded  in 
amoebic  dysentery. 

Yellow  Fever. — Cabot  found  a  polymorph  leucocytosis  in  some  cases, 

1  Biernacki,  Deutsch.  med.  Wochenschr.,  1895,  795. 

2  Rogers,  Lancet,  1902,  659. 

3  Rogers,  Cholera  and  its  Treatment,  London,  1911. 

4  Rogers,  Dysenteries,  Oxford  Medical  Publications,  1913. 


INFECTIOUS   DISEASES  285 

not  in  others.     Eosinophils  were  diminished.     Seidelin  has  described 
protozoon-like  bodies  in  the  blood. 

Dengue. — Red  cells  are  not  much  altered.  Leucopenia  (diminution 
of  polymorphs)  seems  to  be  constant.  There  may  be  eosinophilia  late 
in  the  disease.1 

Bubonic  Plague. — According  to  Sogers  the  blood  changes  met  with 
are  of  some  practical  importance,  but  are  too  inconstant  to  be  absolutely 
relied  on.  Haemoglobin  and  red  cells  are  not  usually  diminished  and 
may  be  increased.  A  slight  leucocytosis  is  generally  present  in  the 
first  three  days,  but  may  be  absent  later,  especially  in  favourable  cases. 
The  proportion  of  lymphocytes  is  frequently  but  not  constantly  increased. 
Bacilli  have  been  found  in  films  of  the  blood. 

Malta  Fever. — Anaemia  may  be  developed.  The  leucocytes  are 
usually  unaffected  or,  in  the  long-standing  cases  which  we  see  in  this 
country,  may  be  diminished.  The  micrococcus  melitensis  can  be  found 
in  the  blood,  and  the  cocci  are  agglutinated  by  the  serum  of  Malta  fever 
patients. 

Anthrax. — Few  observations  have  been  made.  Leucocytes  increase 
to  10,000  or  even  50,000.  Eosinophils  disappear  after  the  fourth 
day. 

Tetanus. — Eed  corpuscles  are  diminished.  Luna  found  leucocytosis 
of  polymorphic  type  (20,000-38,000).  In  all  our  cases  there  has  been 
leucocytosis,  but  the  counts  have  not  been  so  high.  Glycogen  reaction 
was  absent.     Cabot  in  a  fatal  case  found  persistence  of  eosinophils. 

Glanders. — Cases  with  leucocytosis  of  13,000  and  16,000  have  been 
recorded. 

Hydrophobia. — Polymorph  leucocytosis  has  been  found  in  man  and 
animals.  Leucocytosis  is  induced  by  antirabic  treatment,  and  France 
has  noted  an  increase  (2'4  per  cent.)  of  mast  cells. 

Beri-beri. — In  an   acute  case  Takasu 2  found  a  few  normoblasts. 

1  See  Folia  Hcematologica,  iii.  618,  and  v.  477. 

2  See  Folia  Hasmatologica,  i.  1904,  501,  502. 


286 


INFECTIOUS   DISEASES 


White  cells  were  not  much  altered.     In  six  cases  in  Chinese  sailors 
Marshall1  found  no  aneemia  and  no  alteration  of  white  cells. 

Tuberculosis. — In  a  disease  with  such  various  manifestations  and 
with  such  varying  relationships  between  virulence  of  infection  and 
resistance  of  the  tissues  it  is  not  surprising  to  find  great  variations 
in  the  blood  in  different  cases  and  stages  of  the  disease.  It  may- 
be stated  as  the  rule  that  in  uncomplicated  tuberculosis  there  is  a 
diminution  of  red  cells  and  haemoglobin  and  an  increase  of  lympho- 
cytes, which  may  be  balanced  by  a  corresponding  diminution  in 
the  number  of  polymorphs.  Glycogen  reaction  is  absent.  Tubercle 
bacilli  can  be  demonstrated  in  the  blood  in  some  cases,  but  the  pro- 
cedure is  difficult  and  the  results  uncertain.  Injections  of  tuberculin 
are  followed  by  an  increased  leucocyte  count.  There  is  an  increase  of 
neutrophils  and  frequently  also  of  lymphocytes. 

The  diagnosis  of  cases  of  continued  fever  without  very  definite 
physical  signs  is  often  by  no  means  simple.  The  chief  conditions  giving 
rise  to  difficulty  are  typhoid  fever,  influenza,  chronic  septicaemia  and 
deep-seated  abscess,  lymphadenoma  with  enlargement  of  internal 
glands  only,  and  tuberculosis.  The  existence  of  typhoid  can  be  ascer- 
tained by  the  middle  or  end  of  the  second  week  by  means  of  the  Widal 
reaction,  but  it  may  not  be  possible  to  distinguish  between  tuberculosis, 
early  typhoid,  and  influenza  by  ordinary  methods  of  blood  examination. 
The  other  conditions  are  all  associated  with  a  leucocytosis  varying  in 
degree  with  the  severity  of  infection  and  the  resistance  of  the  patient. 

An  increasing  amount  of  importance  is  being  attached  to  Arneth's 
method  as  a  guide  to  diagnosis  and  prognosis  (page  76). 

White  Eobertson  maintains  that  the  Arneth  blood-picture  is  not 
affected  by  such  conditions  as  acute  and  chronic  sepsis,  pneumonia, 
influenza,  typhoid,  dysentery,  and  mucous  colitis  whether  there  be  a 
leucocytosis  or  leucopenia.  He  gives  the  following  figures  from  cases  of 
pulmonary  tuberculosis : — 


Class. 

I. 

II. 

III. 

IV. 

V. 

Normal          ....... 

5 

35 

41 

17 

2 

Early  case     . 

18 

36 

40 

6 

2 

,,          (improved)  . 

6 

38 

45 

11 

0 

Moderate  case 

26 

39 

29 

6 

0 

„            (improving) 

10 

46 

36 

8 

0 

Advanced  case 

31 

49 

17 

3 

0 

Dying  case     . 

65 

33 

2 

0 

0 

1  Edin.  Med.  Joum.,  May  1911. 


INFECTIOUS   DISEASES  287 

1.  Acute  Miliary  Tuberculosis. — The  red  cells  are  usually  not  much 
affected,  but  there  may  be  a  moderate  degree  of  anaemia.  There  is 
generally  a  marked  diminution  in  the  number  of  leucocytes,  and  the 
decrease  affects  lymphocytes  and  eosinophils  rather  than  polymorphs. 

2.  Acute  Pneumonic  Phthisis. — Patients  are  generally  anaemic  from 
the  first  or  soon  develop  anaemia.  The  leucocyte  count  is  usually  below 
normal,  and  continues  low  throughout.  This  low  count  may  be  the  first 
intimation  to  the  attendant  that  the  disease  is  not  the  true  pneumonia 
which  it  often  so  closely  resembles. 

3.  Pulmonary  Phthisis. — (a)  In  early  stages  the  blood  may  show 
little  change,  but  anaemia  of  varying  degree  is  common.  It  is  usually 
slight,  but  may  be  severe  enough  to  give  rise  to  symptoms.  These 
symptoms,  especially  in  young  women,  may  indeed  lead  to  the  real 
state  of  affairs  being  overlooked,  and  true  chlorosis  and  tuberculosis 
may  co-exist.  In  tubercular  anaemia  the  colour  index  is  very  rarely  so 
low  as  in  chlorosis,  and  with  open-air  treatment  we  have  usually  found 
the  blood  return  to  normal  in  cases  that  were  doing  well,  without  the 
necessity  of  giving  iron.  The  leucocytes  are  usually  diminished  in 
number,  the  polymorphs  especially  being  affected.  The  eosinophils 
show  no  constant  change.     The  glycogen  reaction  is  absent. 

(b)  In  the  intermediate  stages  ansemia  is  not  so  constant  a  feature 
as  at  the  outset,  and  changes  in  the  number  of  red  corpuscles  and 
percentage  of  haemoglobin  are  of  more  service  as  an  indication  of 
the  progress  of  the  disease.  The  leucocyte  count  varies,  but  leucopenia 
with  relative  lymphocytosis  is  the  rule. 

(c)  In  advanced  cases  there  is  practically  always  a  diminution  in 
the  number  of  red  cells  and  a  proportionately  greater  reduction  in  the 
percentage  of  haemoglobin.  Polymorphs  become  increased  and  the 
total  leucocyte  count  may  be  a  high  one  in  hectic  cases  as  long  as  there 
is  some  power  of  resistance.  Eosinophils  are  greatly  diminished  or 
absent.  The  glycogen  reaction  may  be  well  marked.  These  white  cell 
changes  are  the  result  of  the  septic  rather  than  the  tuberculous  infection. 

4.  Pleurisy — Peritonitis — Pericarditis. — Anaemia  may  occur,  but  is 
not  necessarily  a  feature  of  these  conditions.  The  white  cells  are  either 
unaffected  or  there  is  a  lymphocytosis,  relative  or  absolute.  An  important 
diagnostic  point  is  the  absence  of  any  increase  of  polymorphs  which 
accompanies  inflammations  of  the  serous  membranes  due  to  most  other 
causes. 

5.  Tuberculous  Meningitis. — Anaemia  advances  with  the  progress  of 
the  disease,  but  is  seldom  marked.     As  distinguished  from  other  forms 


288  INFECTIOUS  DISEASES 

of  tuberculosis,  an  increased  leucocyte  count  is  the  rule.  A  count  of 
12,000  in  the  first  week  is  very  commonly  met  with.  The  increase 
is  mainly  due  to  polymorphs.  There  is  occasionally  a  slight  glycogen 
reaction,  hut  never  so  marked  as  in  meningitis  due  to  other  organisms. 
There  are  some  cases  in  which  the  leucocyte  count  is  not  raised,  especially 
early  in  the  case,  but  the  polymorph  percentage  is  usually  high. 

6.  Tuberculosis  of  Bones  and  Joints. — As  long  as  mixed  infection  is 
absent  there  is  no  change  in  the  red  cells.  The  white  cells  may  show 
no  change  or  there  may  be  lymphocytosis,  relative  or  absolute.  The 
absence  of  any  polymorph  increase  may  be  of  diagnostic  importance. 

7.  Tuberculous  Adenitis. — The  changes  described  above  apply  to 
this  condition. 

8.  Tuberculosis  of  the  Alimentary  and  Genito- Urinary  Tracts. — As 
a  rule  the  blood  shows  little  change,  and  examination  of  the  blood 
gives  little  help  in  diagnosis.  There  may  be  secondary  ansemia 
according  to  the  severity  of  the  condition,  especially  if  there  be 
haemorrhage.  As  regards  the  white  cells,  the  absence  of  retention  and 
consequent  absorption  of  toxins  tend  towards  a  negative  blood-picture, 
even  when  a  mixed  infection  is  present. 

Syphilis.  —  There  is  no  appreciable  change  in  the  primary  stage. 
Diminution  of  red  cells  and,  to  a  greater  extent,  of  haemoglobin  is  prac- 
tically always  a  feature  of  the  secondary  stage.  There  is  generally 
a  definite  increase  in  the  white  cells,  the  lymphocytes  being  chiefly 
involved.  Eosinophils  are  not  diminished.  In  cases  with  no  actual 
leucocytosis  there  is  a  relative  lymphocytosis.  The  administration  of 
mercury  causes  an  increase  of  red  cells,  haemoglobin,  and  of  polymorphs, 
an  effect  which  may  persist  for  a  fortnight  or,  in  some  cases,  even 
for  a  month.  After  that  period  the  mercury  loses  its  stimulating 
effect  on  the  bone-marrow,  and  may  even  begin  to  cause  gelatinous 
degeneration. 

Cases  of  tertiary  syphilis  often  afford  very  marked  examples  of 
secondary  anaemia.  There  may  be  very  great  reduction  in  the  number 
of  red  cells  and  the  amount  of  haemoglobin.  Normoblasts  and  even 
a  few  megaloblasts  may  be  present.  There  is  usually  a  leucocytosis 
with  a  high  percentage  of  lymphocytes,  and  a  few  myelocytes  are 
frequently  to  be  found.  The  spirochaeta  pallida  can  be  found  in  the 
blood  in  secondary  syphilis  and  in  infants  suffering  from  congenital 
syphilis.  As  a  rule  a  fairly  large  amount  of  blood  must  be  taken  and 
mixed  with  ten  times  its  volume  of  I  per  cent,  acetic  acid.     This  is 


INFECTIOUS   DISEASES  289 

c  entrifuged,  and  films  are  made  from  the  deposit.  After  drying  in  air 
films  should  be  fixed  with  absolute  alcohol  or  alcohol-ether  for  from 
ten  to  twenty  minutes,  or  in  methyl  alcohol  for  five  minutes.  Staining 
may  be  carried  out  by  Giemsa's  method  (Giemsa  1  in  15  for  an  hour). 
Leishman's  method  also  gives  good  results  after  prolonged  staining. 
Silver  methods  or  any  of  the  methods  for  demonstrating  flagella  may 
be  employed. 

A  more  simple  method  of  demonstration  is  Burri's.  Some  of  the 
deposit  is  mixed  with  an  equal  quantity  of  a  solution  of  Indian  ink 
in  distilled  water,  a  smear  is  made  on  a  slide  and  allowed  to  dry, 
the  spirochetes  stand  out  white  on  a  dark  background.  Still  another 
method  is  by  means  of  the  dark-ground  illumination. 

Leprosy. — The  data  are  scanty.  Anaemia  is  not  marked  until  severe 
lesions  or  complications  have  developed.  There  is  no  increase  in  the 
number  of  leucocytes.  There  is  a  relative  increase  of  cells  of  the 
lymphocyte  series.  The  weight  of  evidence  is  that  eosinophils  and 
basophils  are  not  increased.  The  bacilli  have  been  found  in  the 
blood. 

Actinomycosis. — Ewing  and  Cabot  report  cases  with  20,000  and 
30,000  leucocytes  per  c.mm. 

Blastomycosis. — In  a  case  affecting  the  lungs  and  alimentary  canal 
we  found  3,720,000  red  corpuscles,  55  per  cent,  haemoglobin,  and  8200 
leucocytes,  of  which  76  per  cent,  were  polymorphs,  24  lymphocytes.  No 
eosinophils  were  seen. 


19 


CHAPTER  XXXI 

SEPTIC  AND  INFLAMMATORY  CONDITIONS 

Introduction. — In  these  conditions  the  blood  may  be  slightly  or  pro- 
foundly altered,  according  to  the  severity,  extent,  and  duration  of  the 
process. 

There  is  always  anaemia,  which  may  be  induced  very  rapidly.  In 
severe  cases  there  are  marked  degenerative  changes  in  the  red  cells,  and 
normoblasts  are  found  in  the  peripheral  circulation. 

Leucocytosis  is  the  rule.  Other  things  being  equal,  a  suppurative 
inflammation  is  associated  with  a  greater  leucocyte  count  than  a  plastic 
process.  The  absorption  of  toxins  is  an  important  factor.  An  unopened 
abscess  of  small  dimensions  is  associated  with  a  greater  leucocytosis  than 
a  drained  empyema.  Leucocytosis  is  generally  absent  in  cystitis.  A 
progressive  inflammation  may  cause  a  greater  leucocytosis  than  a  walled- 
off  abscess.  The  common  pyogenic  cocci  usually  cause  greater  leuco- 
cytosis than  other  organisms.  The  pyogenic  infections  are  associated 
with  the  glycogen  reaction  in  the  leucocytes.  Blood-plates  are  generally 
increased. 

While  the  leucocytosis  associated  with  septic  and  inflammatory  conditions 
is  usually  accounted  for  by  an  increase  of  neutrophil  polymorphs  there  appear 
to  be  certain  exceptions.  Thus  Cabot 1  has  recorded  cases  of  wound  infection, 
boils,  and  septic  adenitis  with  high  lymphocyte  percentages.  One  case  with 
a  total  count  of  20,000  had  70  per  cent,  and  another  with  30,500  had  75  per 
cent,  of  lymphocytes.  Two  cases  with  low  total  counts  (boils  with  3400  and 
streptococcus  throat  infection  with  3600)  had  82  per  cent,  and  62  per  cent,  of 
lymphocytes  respectively.  No  reason  for  the  substitution  of  lymphocytes 
for  neutrophils  could  be  found.  Again,  Michael  Clarke 2  has  reported  a  case 
of  fatal  septicaemia  due  to  infection  with  B.  pyocyaneus  where  the  neutro- 
phils were  51  per  cent.,  lymphocyte  group  (chiefly  large  mononuclears)  46  per 
cent.,  total  count  14,000. 

Septicaemia — Septic  Anaemia. — In  conditions  of  generalised  sepsis 

1  Amer.  Journ.  Med.  Sci.,  March  1913. 

2  Med.  Press,  7th  May,  1913. 

290 


SEPTIC   AND   INFLAMMATOEY   CONDITIONS  291 

or  absorption  of  septic  products  in  such  affections  as  malignant 
endocarditis  or  puerperal  fever  the  blood  changes  are  profound.  The 
blood  as  it  exudes  looks  pale  and  watery.  The  plasma  is  often  tinged 
with  haemoglobin.  The  fibrin  network  is  increased.  The  number  of 
red  cells  is  diminished,  and  may  fall  to  1,000,000  per  c.mm.  The  fall  is 
often  very  rapid.  We  have  known  the  numbers  fall  from  normal  to 
2,500,000  on  the  third  day  after  an  operation,  followed  immediately  by 
sepsis.  A  proportion  of  the  red  cells  are  often  larger  than  in  other 
forms  of  secondary  anaemia,  and  may  be  larger  than  normal.  This  fact 
along  with  the  hsemoglobinsemia  would  appear  to  suggest  some  dilution 
of  the  plasma.  There  is  considerable  diversity  of  size.  Poikilocytosis 
is  not  a  marked  feature  in  acute  cases  but  is  very  conspicuous  in  chronic 
forms. 

There  is  generally  a  fair  degree  of  diffuse  polychromasia.  Punctate 
basophilia,  though  often  present,  is  not  such  a  marked  feature.  Haemo- 
globin is  always  diminished.  The  colour  index  may  be  very  low,  the 
average  being  about  0*6,  but  in  acute  cases  it  is  higher,  and  tends  to  rise 
as  the  anaemia  increases. 

Normoblasts  occur  with  some  frequency  in  acute  cases  when  the 
count  has  fallen  below  2,500,000,  but  are  rare  with  higher  counts  and 
in  chronic  cases.  Megalolasts  may  be  said  not  to  occur.  The  large  red 
cells  which  are  found,  and  on  whose  presence  the  rise  of  colour  index 
probably  depends  in  great  measure,  do  not  attain  the  size  of  megalocytes, 
and  the  condition  of  the  red  cells  should  not  lead  to  a  mistaken  diagnosis 
of  pernicious  anaemia.  Even  in  the  worst  cases  the  colour  index  rarely 
rises  above  0"8. 

Leucocytes. — The  number  of  leucocytes  varies  with  the  relationship 
of  the  infection  to  the  resistance  of  the  body.  As  long  as  the  patient 
is  not  overwhelmed  by  the  toxins  there  will  be  a  leucocytosis.  A  high 
leucocytosis  by  no  means  indicates  a  favourable  termination,  but  absence 
of  leucocytosis  or,  more  particularly,  leucopenia  in  a  severe  case  is  a 
certain  indication  of  a  fatal  prognosis.  The  leucocyte  increase  is  caused 
by  polymorphs.  Myelocytes  frequently  appear,  and  are  of  grave  signifi- 
cance as  indicating  that  the  powers  of  the  marrow  are  becoming 
exhausted.  The  polymorphs  show  a  definite  glycogen  reaction.  Their 
neutrophil  granules  often  stain  with  special  intensity,  but  many, 
evidently  degenerated,  will  be  found  in  which  both  nucleus  and  granules 
stain  badly. 

Eosinophils  are  always  diminished  and  often  altogether  disappear. 
Blood-plates  are  usually  increased.    In  a  large  proportion  of  cases  micro- 


292         SEPTIC   AND   INFLAMMATOKY   CONDITIONS 

organisms  may  be  cultivated  from  the  blood,  especially  if  it  be  examined 
in  the  early  days  of  the  disease. 

Appendicitis. — Unless  the  condition  extends  to  such  a  degree  as  to 
fall  into  the  category  of  septicaemia,  the  red  cells  are  not  affected,  beyond 
a  trivial  anaemia  in  long-standing  cases.  The  condition  of  the  leucocytes 
is  of  prime  significance  in  diagnosis  and  prognosis,  and  as  a  factor  in 
determining  the  advisability  of  operation. 

In  "  foudroyant "  cases  and  in  all  cases  of  great  severity  in  which  the 
patient  is  rapidly  and  intensely  poisoned  there  is  no  leucocytosis  and 
may  indeed  be  a  leucopenia.  The  polymorph  proportion  may  be  high, 
but  it  is  not  uncommon  to  find  it  between  60  and  70,  or  even  lower. 
The  glycogen  reaction,  however,  is  always  very  marked. 

In  slight  catarrhal  cases  the  'count  is  rarely  quite  normal.  There  is 
usually  a  slight  leucocytosis,  perhaps  10,000  or  12,000.  The  polymorph 
percentage  is  not  high,  rarely  above  75,  and  the  glycogen  reaction  may  be 
absent,  doubtful,  or  very  slight.  In  severer  cases  the  range  of  the  count 
is  wide.  The  higher  the  count  the  more  definite  the  indication  for  opera- 
tion. Cases  with  a  count  of  20,000  or  above  rarely,  if  ever,  deserve  to 
escape  operation,  though  they  sometimes  recover  without  it.  Counts  of 
25,000  or  anything  above  that  indicate  immediate  operation  in  all  cases. 
Gangrene,  peritonitis,  or  suppuration  are  practically  always  present. 

The  great  difficulty  in  utilising  the  leucocyte  count  in  appendicitis 
lies  in  the  fact  that  in  the  great  majority  of  cases  the  count  is  about 
15,000  to  17,000,  even  though  the  local  condition  is  severe.  The 
explanation  of  this  probably  lies  in  the  character  of  the  organisms  con- 
cerned. They  are  usually  those  of  the  coli  group,  to  which  the  body  is 
more  or  less  accustomed,  and  which  do  not  cause  a  great  marrow 
reaction.  When  the  pus-producers  are  present  in  addition  the  reaction 
is  generally  greater.  With  counts  of,  say,  17,000  in  the  absence  of 
definite  signs  or  symptoms  indicating  operation  or  delay,  weight  should 
be  given  to  the  polymorph  proportion  and  the  intensity  of  the  glycogen 
reaction.  A  polymorph  proportion  of  75  to  80  with  a  slight  glycogen 
reaction  would  indicate  a  slight  case,  while  a  percentage  of  85  or  over 
with  a  marked  glycogen  reaction  would  mean  a  severe  one.  It  is  further 
to  be  noted  that  if  the  polymorph  proportion  and  glycogen  reaction  seem 
to  run  counter  to  one  another,  more  stress  is  to  be  laid  as  a  rule  on  the 
polymorph  proportion,  for  the  organisms  of  the  coli  group,  which  are 
usually  involved,  do  not  cause  so  marked  a  glycogen  reaction  as  the 
pus  producers. 


Plate  XIV. 


-Severe  Secondary  (Septic)  Anaemia  prom  a  Case  of 
Ulcerative  Endocarditis. 


Hud  corpuscles  are  deformed  and  polychromasic.     There  are  two  normoblasts,  one  with  marked 

polychromatophilia.     One  erythrocyte  shows  basophilic  stippling. 
Polymorphonuclear  neutrophils  are  increased.     One  myelocyte  is  present. 
Blood-plates  are  increased. 


A.  G.,feciL 


SEPTIC   AND   INFLAMMATORY   CONDITIONS  293 

If  a  single  count  is  valuable,  much  more  valuable  is  the  result  of 
repeated  counts  in  individual  cases.  A  rising  count  indicates  an 
advancing  inflammation,  a  definitely  failing  count,  if  the  patient's 
condition  be  improving,  means  subsidence  of  the  inflammation,  but  if  the 
patient  be  worse,  means  that  he  is  more  poisoned,  and  generally  that 
operation  has  been  too  long  deferred.  A  stationary  leuocytosis  often 
means  that  an  abscess  is  being  walled  off,  and  it  must  be  remembered 
that  in  these  cases  the  polymorph  percentage  may  not  be  so  high  and 
glycogen  reaction  not  so  marked  as  one  would  expect  them  to  be  from 
the  height  of  the  count  and  from  the  patient's  condition.  In  any  case, 
however,  a  stationary  leucocytosis  may  be  taken  as  an  indication  for 
operation. 

It  must  be  understood  that  the  foregoing  only  applies  to  cases  in 
which  there  is  clinically  no  doubt  of  the  diagnosis  of  appendicitis.  It 
must  not  be  forgotten  that  acute  catarrhal  inflammations  of  the  bowel 
may  often  cause  a  much  higher  leucocytosis  than  is  usual  in  appendicitis, 
and  that  pyosalpinx  may  give  rise  to  exactly  the  same  changes  in  the 
blood  as  appendicitis,  while  all  the  bowel  conditions  which  are  likely  to 
be  mistaken  for  appendicitis,  may  sometimes  cause  leucocytosis.  The 
blood-plates  and  fibrin  network  are  increased. 

Salpingitis. — What  has  been  said  about  appendicitis  applies  to  this 
condition.  The  leucocytosis  may  aid  greatly  in  diagnosing  a  pyosalpinx 
from  hydrosalpinx,  ectopic  gestation,  or  tubercle. 

Abscess. — The  leucocyte  count  is  raised  in  all  cases  of  septic  abscess. 
The  increase  is  purely  polymorphonuclear.  In  a  purely  tuberculous 
abscess,  leucocytosis,  if  it  exists,  is  determined  by  a  lymphocyte  increase. 
When  a  septic  abscess  is  opened  the  leucocytosis  rapidly  diminishes  in 
most  cases,  but  where  acute  inflammatory  changes  persist,  as  in  many 
cases  of  whitlow,  the  leucocyte  increase  is  correspondingly  maintained. 
The  leucocyte  count  with  the  glycogen  reaction  is  an  important  guide  to 
the  efficiency  of  drainage. 

Boil  and  Carbuncle. — The  leucocyte  count  in  these  conditions  is 
greatly  increased  and  the  polymorph  percentage  is  correspondingly  high. 
The  glycogen  reaction  is  intense. 

Osteomyelitis. — Leucocytosis  is  generally  considerable,  and  is  of 
diagnostic  value.     Differential  counts  show  the  usual  polymorph  increase. 


294         SEPTIC   AND   INFLAMMATORY   CONDITIONS 

The  occasional  difficulty  which  occurs  in  diagnosing  this  condition  from 
acute  articular  rheumatism  can  be  avoided  by  examining  the  blood. 
In  osteomyelitis  the  leucocytosis  is  usually  higher  than  the  12,000  or 
15,000  of  acute  rheumatism;  the  polymorph  proportion  is  80  or  over; 
the  glycogen  reaction  is  marked.  In  acute  rheumatism  the  polymorphs 
number  as  a  rule  less  than  80  per  cent,  in  uncomplicated  cases,  and 
the  glycogen  reaction  is  negative. 

Otitis  Media. — Darling1  examined  sixty-six  cases.  The  average 
count  in  uncomplicated  cases  was  11,000,  with  69  per  cent,  of  polymorphs. 
With  mastoid  complication  the  average  figures  were  12,000,  with  73  per 
cent,  of  polymorphs.  No  case  without  intracranial  complication  was 
found  to  have  more  than  86  per  cent,  of  polymorphs,  and  no  case  with 
intracanial  complication  had  a  less  percentage  than  77.  After  operation 
there  was  generally  a  rise  (average  8000)  in  the  number  of  polymorphs. 
This  passed  off  within  four  days.  The  glycogen  reaction  is  present* 
but  as  the  presence  of  pus  is  not  in  doubt  it  is  of  little  diagnostic 
value. 

When  there  is  any  question  of  generalised  infection  or  of  the  necessity 
or  otherwise  of  tying  the  jugular  vein,  blood  cultures  may  give  results  of 
great  value.2 

Gonorrhoea. — There  is  no  very  striking  change  in  the  blood  in  the 
ordinary  acute  cases.  Leucocytes  may  be  slightly  increased,  the  increase 
affecting  the  polymorphs.  In  most  cases  there  appears  to  be  a  slight 
increase  of  eosinophils  corresponding  with  the  invariable  presence  of 
eosinophils  in  the  pus.  In  gonorrhceal  septicaemia  there  is  a  poly- 
morphonuclear leucocytosis,  and  in  some  of  the  few  cases  recorded 
the  gonococcus  has  been  cultivated  from  the  blood. 

Erysipelas. — In  mild  cases  slight  increase  of  polymorphs  is  the  only 
change ;  in  more  severe  cases  the  increase  may  be  considerable.  The 
range  might  be  put  at  12,000  to  20,000.  The  latter  figure  is  rare. 
The  count  falls  a  day  or  two  after  the  fever  has  subsided.  A  relapse 
is  often  preceded  by  a  sharp  rise  in  the  leucocyte  count.  Eosinophils 
usually  disappear.  The  fibrin  network  is  increased,  and  there  is  some 
increase  in  the  number  of  blood-plates. 

Pleurisy — Pericarditis — Peritonitis. — The  blood  varies  in  accord- 

1  Ellin.  Med.  Journ.,  1908. 

2  See  Libnian  and  Celler,  Amer.  Journ.  of  Med.  Sci.,  September  1909. 


SEPTIC  AND    INFLAMMATORY   CONDITIONS         295 

ance  with  many  factors  in  these  conditions.  An  acute  rheumatic  affection 
of  any  kind  will  bring  about  a  polymorph  leucocytosis,  with  an  increase 
of  fibrin  and  blood-plates.  As  already  stated,  a  micrococcal  infection 
will  bring  about  similar  changes,  while  a  tuberculous  condition  will  be 
associated  either  with  no  special  blood  change  or  with  a  lymphocytosis, 
relative  or  absolute.  A  dropsical  effusion  is  not  accompanied  by  any 
blood  change.  In  acute  infections  the  degree  of  leucocytosis  is  probably 
an  index  of  the  severity  of  the  process,  but  gives  no  clue  to  the  differen- 
tiation of  the  causal  condition.  The  occurrence  of  a  sharp  rise  of  the 
leucocyte  count  in  pleurisy  may  indicate  that  empyema  has  supervened. 
This  will  be  practically  certain  if  the  glycogen  reaction  either  appears 
or,  if  already  present,  becomes  more  intense. 


CHAPTER  XXXII 

MALIGNANT  DISEASE— WOUNDS   AND   FRACTURES- 
POISONS 

Malignant  Disease. — In  early  cases  the  usual  blood-picture  is  simply 
a  polymorph  increase.  In  a  fair  number  of  cases  there  is  merely  an 
alteration  in  proportions,  so  that  without  increase  in  the  total  numbers 
there  is  a  high  polymorph  percentage — a  so-called  "  relative  (polymorph) 
leucocytosis,"  or,  more  correctly,  a  diminished  number  of  lymphocytes. 
In  a  smaller  number  of  cases,  especially  in  cachexia,  there  is  increase  of 
both  neutrophils  and  lymphocytes,  so  that  their  proportions  are  not 
altered.  A  considerable  number  of  myelocytes  pass  into  the  circulation 
in  cancerous  cachexia.  Degenerative  changes  in  the  leucocytes  are 
common.  These  include  poor  staining  reactions  of  the  polymorph 
granules  and  fraying  of  the  edges  of  the  lymphocytes  with  vacuolation  of 
their  protoplasm.  Sooner  or  later  anaemia  supervenes.  There  is  at  first 
merely  a  diminution  of  haemoglobin  and  consequent  low  colour  index, 
then  the  red  cells  decrease  and  begin  to  exhibit  degenerative  pheno- 
mena, and  the  colour  index  tends  to  rise.  The  average  size  is  reduced. 
There  is  anisocytosis  and  may  be  great  deformity  of  the  cells.  Poly- 
chromasia  becomes  marked.  Normoblasts  and  sometimes  megaloblasts 
appear  in  the  blood.  Blood-plates  are  often  fairly  numerous.  Eibrin 
tends  to  be  diminished.  There  is  often  a  slight  amount  of  haemo- 
globinaemia,  and  in  advanced  cases  the  glycogen  reaction  makes  its 
appearance,  probably  due  to  secondary  infection.  In  cachexia  the 
leucocyte  increase  may  be  considerable.  Cancer  affecting  internal 
organs  is  more  likely  to  be  associated  with  leucocytosis  than  cancer  of 
external  parts.  Rapidly -growing  tumours  and  tumours  with  metastases 
are  more  likely  to  be  associated  with  leucocytosis  than  slow-growing  or 
localised  tumours.  Enormous  numbers  of  nucleated  red  cells  may  be 
present  in  cases  of  bone-marrow  metastases.  In  this  condition  the 
blood-picture  may  closely  resemble  that  of  pernicious  anaemia.  Anaemia 
may  become  profound,  megalocytes  may  be  numerous,  and  the  colour 
index  may  become  high.  Numerous  myelocytes  may  make  their  appear- 
ance.    As  a  rule  there  is  leucocytosis,  but  this  may  fail.     The  diagnosis 


MALIGNANT   DISEASE  297 

from  actual  pernicious  anaemia  may  then  be  very  difficult.     Pain  and 
tenderness  in  the  bones  is  generally  greater  than  in  pernicious  anaemia. 
Sarcoma  as  a  rule  causes  more  intense  leucocytosis  than  carcinoma. 
In  a  few  cases  there  is  a  very  marked  eosinophilia. 

Cancer  of  the  (Esophagus. — Owing  to  malnutrition  there  is  more  likely 
to  be  a  diminution  than  an  increase  of  white  cells.  Anaemia  soon 
becomes  established  and  acquires  the  features  described  above. 

Cancer  of  the  Stomach. — Before  ulceration  occurs  leucocytes  may  be 
low  as  in  other  malnutritions.  After  ulceration,  when  haemorrhage 
readily  occurs,  there  may  be  very  high  counts,  but  one  cannot  depend 
upon  these,  as  the  factor  of  malnutrition  seems  to  remain  the  pre- 
dominating one.  There  is  no  definite  information  to  be  gained,  therefore, 
from  the  blood  in  the  diagnosis  between  cancer  and  ulcer.  No  condition 
is  more  frequently  confused  with  pernicious  anaemia  (q.v.),  as  the  anaemia 
resulting  from  malnutrition,  cachexia,  and  haemorrhage  combined  is  often 
severe. 

Cancer  of  the  Liver  and  Pancreas. — There  is  always  leucocytosis  and 
the  glycogen  reaction.  This  fact  often  adds  to  the  difficulty  in  diagnosis 
between  cancer  of  the  liver  and  inflammatory  and  suppurative  processes 
in  and  about  it.  Cancer  appears  to  interfere  greatly  with  the  function 
of  the  liver  as  a  destroyer  of  intestinal  toxins.  They  pass  into  the  general 
circulation,  probably  cause  the  glycogen  reaction  and  at  least  part  of 
the  leucocytosis,  and  very  often  give  rise  to  fever. 

Cancer  of  the  Kidney  and  Suprarenal. — Leucocytosis  is  practically 
always  present. 

Cancer  of  the  Uterus. — A  slight  leucocytosis  may  be  present  from 
the  first.     After  haemorrhages  the  counts  may  be  high. 

Cancer  of  the  Breast. — As  far  as  the  blood  is  affected  this  may 
be  considered  as  an  external  cancer,  with  little  change  in  early 
cases.  Advanced  cases  or  cases  with  metastases  show  typical  blood 
changes. 

Mediastinal  Lymphosarcoma. — In  many  cases  leucocytosis  is  very 
slight  or  altogether  absent.  Its  presence  may  be  of  great  service  in 
the  differential  diagnosis  between  solid  neoplasm  and  aneurysm. 

Significance  of  the  Blood  Changes  in  Cancer. — The  anaemia  and 
degenerative  changes  are  to  be  regarded  as  a  measure  of  the  toxaemia, 
unless  haemorrhage  is  a  marked  feature.  Blood  regeneration  is  at  a  low 
ebb  in  cancer,  and  does  not  take  place  so  rapidly  or  fully  as  in  health. 
As  a  matter  of  practical  diagnostic  importance  the  examination  of  the 
blood  in  many  cases  gives  disappointing  results,  but  occasionally  affords 


298  FEACTUEES— WOUNDS 

positive  evidence  of  great  value.  In  the  case  of  a  deep-seated  lesion 
leucocytosis  will  indicate  in  favour  of  suppuration  or  malignant  disease 
rather  than  of  one  of  the  granulomata.  The  presence  of  a  marked 
glycogen  reaction  would  then  distinguish  suppuration  from  a  compara- 
tively early  neoplasm.  Eosinophilia  might  indicate  the  likelihood  of 
hydatids,  but  is  sometimes  seen  in  sarcomata  and  fairly  often  in 
malignant  ovarian  disease.  Leucocytosis,  when  present,  is  an  impor- 
tant help  in  distinguishing  between  mediastinal  tumour  and  aneurysm. 
A  tumour  being  diagnosed,  leucocytosis  indicates  a  malignant  rather 
than  a  simple  type,  and  a  progressive  leucocytosis  probably  indicates 
a  corresponding  progress  in  tumour  growth  or  metastasis.  Digestion 
leucocytosis  is  often  absent  in  cancer  of  the  stomach  and  elsewhere,  but 
this  phenomenon  is  not  constant,  and  may  occur  in  other  conditions. 

Literature 

Baradulin,  Folia  Hcematologica,  ix.  1  Teil,  1910,  407  (general  account;. 
Barrington  and  Kennedy,  Lancet,  8th  February  1913  (bone-marrow 
metastases). 

Fractures — Wounds 

Fractures. — In  simple  fracture  there  is  a  slight  leucocytosis  during 
the  first  three  days,  due  to  an  increase  of  polymorphs  and  large  lympho- 
cytes. In  compound  fractures  the  blood  changes  are  complicated  by 
haemorrhage  and  the  nature  of  the  wound. 

Simon  {American  Journ.  of  the  Med.  Sciences,  cxxxiii.  1907,  389)  has 
published  a  remarkable  case  in  which  the  typical  blood-picture  of  myelo- 
cythsemia  supervened  in  about  a  fortnight  after  a  complicated  fracture  of 
the  ankle.  The  spleen  became  palpable.  A  month  after  the  injury  the  foot 
was  amputated.  The  leukemic  changes  were  still  present  at  the  end  of  a 
week,  but  had  altogether  disappeared  at  the  end  of  a  month. 

Wounds  and  Aseptic  Operations. — After  a  wound  or  aseptic  opera- 
tion there  is  a  leucocytosis,  which  appears  in  from  six  to  twelve  hours,  and 
is  independent  of  either  anaesthesia  or  haemorrhage,  although  the  effects 
of  these  may  be  superimposed.  Dawson l  could  not  find  any  relation- 
ship between  the  degree  of  leucocytosis  and  the  severity  of  the  operation. 
In  some  aseptic  cases  he  found  a  slight  glycogen  reaction,  and  suggested 
that  the  leucocytosis  may  be  caused  by  micro-organisms,  which  it  is 
impossible  to  exclude  entirely.     Busse,2  on  the  other  hand,  found  a  very 

1Edin.  Med.  Journ.,  November  1905. 
2  Arcliiv  f.  Gyn.,  lxxxv.  1. 


POISONS  299 

distinct  relationship  between  the  degree  of  leukocytosis  and  the  severity 
of  the  operation,  but  his  higher  counts  were  in  cases  of  extensive 
abdominal  or  pelvic  carcinomata.  The  increase  is  in  the  main 
polymorphonuclear,  but  the  large  lymphocytes  may  also  increase  to 
a  less  extent. 

Deugs — Poisons — Anaesthetics 

Hemolytics. — A  large  number  of  substances  act  as  heemolytic 
agents.     Their  action  is  not  in  all  cases  the  same. 

1.  There  is  a  class  which  acts  by  dissolving  hsemoglobin  and  liberating 
it  from  the  corpuscles.  Such  substances  are  distilled  water,  glycerine,  salts 
of  the  bile  acids,  snake  venom,  and  the  serum  of  animals  either  naturally 
or  artificially  antagonistic. 

2.  Another  series  of  substances  act  as  toxic  agents  to  the  red  corpuscles, 
killing  them  but  not  necessarily  leading  to  any  escape  of  haemoglobin  from 
them.  Examples  of  this  group  are  phenyl-hydrazin,  toluylen  -  diamine, 
pyrodin,  amido-benzoic-ethyl-ether,  pyrogallic  and  chromic  acids. 

The  first  group  of  substances  causes  the  immediate  appearance  of  haemo- 
globin in  the  urine  j  the  second  group  may  cause  blood-pigment  to  occur  in 
the  urine,  but  its  appearance  is  delayed,  and  its  amount  is  never  comparable 
to  that  caused  by  the  haemolytics  of  the  first  group.  All  these  substances 
also  cause  leucocytosis.  A  considerable  number  of  substances  which  affect 
the  white  cells  are  referred  to  in  the  chapters  on  Leucocytosis.  Such  sub- 
stances have  been  employed  in  experimental  work,1  but  their  effects  are  not 
likely  to  be  met  with  in  clinical  cases. 

Aniline,  Nitro-benzene  and  its  Compounds,  Acetanilide,  Phena- 
zonum,  and  Phenacetin. — All  these  substances  act  in  much  the  same 
way.  In  excessive  dosage  and  in  cases  of  idiosyncrasy  there  may  be 
cyanosis,  and  the  blood  may  appear  chocolate  coloured  from  the  presence 
of  methfemoglobin  in  the  plasma.  Anaemia  results  and  is  associated 
with  an  increase  of  polymorphonuclear  cells.  There  may  be  a  brief 
primary  leucopenia.  Eosinophils  are  diminished.  There  are  the  usual 
signs  of  secondary  anaemia.  Polychromasia  is  specially  well  marked, 
and  nucleated  red  cells  are  numerous  at  first.  A  few  myelocytes  may 
be  found.  In  cases  which  recover,  regeneration  of  blood  occurs  very 
rapidly. 

Salines. — It  has  been  found   that   saline  cathartics,  especially  if 
given  in  single  massive  closes,  may  concentrate  the  blood  to  such  an 
1  See  Noel  Paton  and  Goodall,  Journ.  of  Physiology,  xxix.  1903,  411. 


300  POISONS 

extent  as   to   cause  a   definite  increase  of  red   corpuscles   per  cubic 
millimetre  in  the  peripheral  circulation. 

Iodides. — There  is  an  increase  of  the  viscosity  of  the  blood  and  a 
slightly  greater  number  of  polymorphs  (Barenczik).1 

Potassium  Chlorate. — Poisoning  may  occur,  especially  in  children. 
The  red  cells  become  broken  down  and  tend  to  be  agglutinated.  Their 
size  is  rather  increased.  Basophilic  staining  is  not  marked.  Poly- 
morphs are  distinctly  increased,  so  that  the  total  leucocytes  per  cubic 
millimetre  may  reach  20,000.  The  other  forms  of  white  cells  tend  to 
be  diminished.     The  after-effects  are  the  usual  regenerative  changes. 

Lead. — Among  lead  workers  it  is  not  uncommon  to  find  a  very 
considerable  increase  in  the  number  of  the  red  corpuscles  and  an 
augmented  haemoglobin  percentage.  There  may  also  be  an  increase 
of  polymorphs.  More  commonly,  however,  the  result  of  chronic  lead- 
poisoning  is  an  anaemia  with  special  characters.  While  in  the  main 
the  features  are  those  of  secondary  anaemia,  the  anaemia  is  remarkable 
firstly  for  the  large  number  of  red  corpuscles  which  show  basophilic 
stippling.  Polychromasia  of  the  diffuse  type  is  not  nearly  so  common. 
The  granular  red  corpuscles  may  amount  to  10  per  cent,  in  cases  with 
severe  symptoms.  Another  special  feature  of  the  blood  in  lead-poison- 
ing is  the  large  number  of  normoblasts  which  are  found.  They  are 
much  more  numerous  than  in  other  secondary  anaemias  of  equal 
severity.  Cadwalader  found  that  the  number  of  stippled  cells  varies 
directly  with  the  number  of  nucleated  red  cells.  A  small  number  of 
megalobasts  make  their  appearance  in  severe  cases.  Leucocytes  are 
increased  in  most  cases,  but  not  invariably. 

Mercury. — In  workers  among  mercury  there  may  be  a  considerable 
increase  of  red  corpuscles  and  of  haemoglobin,  and  leucocytosis.  Anaemia 
frequently  supervenes,  and  has  pretty  much  the  same  characters  as  lead 
anaemia. 

Silver. — Salts  of  silver  and  various  combinations  with  silver  have 
been  found  to  cause  after  injection  into  animals  a  transient  leucopenia, 
followed  by  polymorph  leucocytosis,  which  in  turn  gives  place  to  a 
lymphocytosis  with  eosinophilia  (Folia  Hcematologica,  vii.  1909,  76). 
1  Folia  Hcematologica,  ix. ;  Zentralb.,  1913,  p.  25. 


POISONS  301 

Phosphorus. — In  chronic  cases  or  in  acute  cases  which  survive  there 
is  first  an  increase  of  red  corpuscles  and  a  decided  leucopenia.  This  is 
followed  by  a  slight  diminution  of  the  red  corpuscles  and  hemoglobin, 
and  some  nucleated  red  cells  appear  in  the  blood.  At  the  same  time 
the  leucopenia  gives  place  to  a  moderate  leucocytosis.  The  leucopenia 
is  due  to  diminution  of  polymorphs,  which  have  been  found  as  low  as 
5  per  cent. 

Arsenic. — Arsenical  poisoning  gives  rise  to  practically  the  same 
conditions.  There  may  be  increase  of  the  red  cells.  This  is  followed 
by  their  diminution.  The  leucocytes  may  diminish,  and  later  they 
increase.  If  the  arsenic  be  continued  there  is  a  tendency  for  the 
lymphocytes  to  increase  at  the  expense  of  the  polymorphs.  Atoxyl 
has  given  rise  to  similar  effects. 

Stockman  and  Charteris  (Journ.  of  Path,  and  Bad.,  ix.  1903)  found  that 
lead,  mercury,  and  phosphorus  first  caused  an  increase  of  leucoblastic 
activity  in  the  bone-marrow  with  a  disappearance  of  fat.  This  was  followed 
by  ansemia,  and  later  by  gelatinous  degeneration.  Large  doses  of  mercury 
did  not  cause  the  increase  of  red  cells  that  has  been  found  to  follow  the  use 
of  small  doses. 

Chloral  Hydrate. — After  the  prolonged  use  or  abuse  of  this  drug 
anaemia  with  leucocytosis  has  been  noticed. 

Alcohol. — The  changes  vary.  In  many  cases  of  delirium  tremens 
there  is  a  polymorph  increase.  The  same  finding  is  obtained  in 
alcoholic  multiple  neuritis. 

Quinine. — The  hemoglobinuria  of  blackwater  fever  has  been  attri- 
buted to  the  action  of  quinine,  but  this  is  not  proved.  Large  doses 
cause  leucocytosis.  Stockman  and  Charteris  found  that  it  did  not 
affect  the  bone-marrow. 

Opium. — In  acute  poisoning  the  blood  changes  are  due  to  cyanosis. 
In  opium  eaters  the  blood  is  not  specially  affected. 

Colchicum. — Dixon  and  Maiden  (Journ.  of  Physiol.,  xxxvii.  1908, 
50)  found  that  injections  of  colchicine  caused  a  transient  leucopenia, 
followed  by  a  marked  leucocytosis. 

They  found  that  colchicine  caused  a  polymorph  leucocytosis  in  carnivorous 
animals.     In   herbivora  there   was   lymphocytosis,  followed   by   neutrophil 


302  POISONS 

leucocytosis.  Large  doses  caused  all  the  normal  elements  of  the  bone- 
marrow  to  be  found  in  the  general  circulation.  During  maximum  leuco- 
cytosis marrow  cells  were  scanty  in  bone-marrow  sections.  During  leucopenia 
the  marrow  was  more  cellular.  Small  doses  of  colchicine  caused  an  increase 
of  basophils  without  directly  affecting  the  other  leucocytes. 

Felix  mas  and  Senna. — These  drugs  have  been  found  to  cause  an 
increase  of  polymorphs  and  a  diminution  of  lymphocytes  and  eosino- 
phils in  worm  infections.  Leucocytosis  after  the  administration  of 
senna  has  been  noted  in  other  diseases  (Grek  and  Eeiehenstein).1 

Illuminating  Gas  Poisoning. — The  red  corpuscles  are  not  destroyed, 
but  are  rendered  physiologically  useless  in  large  measure  by  the  fact 
that  haemoglobin  forms  a  more  stable  compound  with  carbon  monoxide 
than  with  oxygen.  The  individual  corpuscles  are  said  to  be  larger 
than  normal  in  acute  cases.  We  have  not  been  able  to  confirm  this  in 
our  cases.  The  red  count  is  therefore  at  first  unaffected,  but  if  the 
patient  survives  it  rapidly  undergoes  an  increase,  since  regeneration 
is  stimulated  before  the  damaged  corpuscles  are  eliminated.  Leuco- 
cyte counts  of  from  15,000  to  30,000  have  been  found.  The  condition 
is  readily  recognised  by  the  bright  red  colour  of  the  blood  and  of 
the  patient's  mucous  membranes,  and  a  definite  diagnosis  can  be  made 
by  means  of  the  spectroscope  in  most  cases. 

Anaesthesia. — In;  the  human  subject  it  is  difficult  to  obtain  uncom- 
plicated results.  The  common  finding,  however,  which  agrees  with 
observations  on  animals,  is  that  a  polymorphonuclear  leucocytosis 
follows  anaesthesia  by  ether,  while  the  leucocytes  are  unaffected  by 
chloroform.  Nitrous  oxide  and  ethyl  chloride  have  practically  no 
effect.2 

1  Wien.  mecl.  Woch.,  1913. 

2  Guy,  Goodall,  and  Reid,  Med.  Press,  1913. 


CHAPTER  XXXIII 

DISEASES    OF   THE    ALIMENTARY   SYSTEM 

Stomatitis. — The  blood  may  be  affected  by  the  causal  condition.  In  the 
simpler  forms  there  is  no  change.  In  parasitic  stomatitis  there  may  be 
a  slight  leucocytosis,  but  counts  in  uncomplicated  cases  have  been  very 
seldom  made. 

Tonsillitis. — In  acute  cases  the  red  cells  are  not  affected.  There  is 
usually  a  high  leucocytosis  accompanied  by  the  changes  found  in  inflam- 
matory conditions.  In  chronic  cases  there  may  be  a  secondary  anaemia  of 
some  severity. 

Obstruction  of  the  (Esophagus. — Simple  and  malignant  cases  alike 
do  not  affect  the  blood  until  malnutrition  causes  a  diminution  of  both 
red  and  white  cells. 

Gastritis. — In  simple  cases  there  is  no  change.  In  the  severer 
cases  the  blood  follows  the  ordinary  course  of  inflammatory  conditions 
in  general. 

Gastric  Ulster. — There  is  always  anaemia  of  secondary  type,  varying 
in  degree.  After  haemorrhage  this  may  be  very  severe.  In  one  case 
which  recovered  the  red  cells  fell  to  800,000  and  the  haemoglobin  to 
5  per  cent  in  two  days.  After  haemorrhage  the  leucocytes  may  of 
course  be  high,  but  ordinarily  there  is  no  increase,  and  there  is  often 
leucopenia. 

Cancer  of  the  Stomach. — See  Chapter  XXXII. 

Duodenal  Ulcer. — The  changes  are  those  found  in  gastric  ulcer,  but 
in  cases  occurring  in  men  in  middle  life  the  anaemia  may  be  trifling  and 
of  little  help  in  diagnosis,  as  it  may  not  exceed  that  resulting  from 
chronic  dyspepsia. 


304  DISEASES   OF  THE   ALIMENTAKY  SYSTEM 

Enteritis  and  Colitis. — There  may  be  a  marked  leucocytosis  in  severe 
acute  cases,  and  this  finding  should  not  be  taken  as  favouring  a  diagnosis 
of  appendicitis  unless  the  above  conditions  can  be  excluded.  25,000  is 
not  an  uncommon  number.  It  is  obvious  that  this  gives  valuable  help 
in  the  diagnosis  from  typhoid.  In  chronic  enteritis  granular  degenera- 
tion of  red  cells  may  be  well  marked,  and  there  is  sometimes  a  high 
percentage  of  lymphocytes  with  a  normal  total  count. 

Appendicitis. — See  Chapter  XXXI. 

Constipation  and  Intestinal  Obstruction. — The  blood  changes  vary 
so  much  with  the  cause  that  they  can  hardly  be  grouped  under  this 
heading. 

Diarrhoea. — In  severe  cases  there  may  be  high  counts  from  con- 
centration of  the  blood.  The  causal  conditions  may  lead  to  alterations 
in  the  number  or  proportion  of  the  white  cells.  In  chronic  cases  there 
may  be  severe  anaemia. 

Sprue. — Ansemia  is  always  a  marked  feature  in  the  later  stages  of 
the  disease,  but  in  severe  attacks  it  may  be  an  early  symptom.  It  is 
generally  of  the  ordinary  type  of  secondary  anaemia,  but  in  a  fair  pro- 
portion of  cases  there  is  a  high  colour  index.  Leucocytes,  especially  the 
polymorphs,  are  greatly  diminished.  Thin  in  his  monograph  on  sprue 
refers  to  the  severe  anaemia  which  occurs,  and  its  resemblance  to 
pernicious  anaemia.     He  quotes  the  following  counts : — 


Red  Cells. 

Haemoglobin. 

Colour  Index. 

1,820,000 

70 

1-9 

2,500,000 

58 

1-1 

2,000,000 

65 

1-6 

three  cases  of  our 

own  the  counts  were — 

Red  Cells. 

Haemoglobin. 

Colour  Index. 

White  Cells. 

(1)     2,280,000 

65 

116 

4600 

(2)     3,630,000 

76 

1-05 

3800 

(3)     4,480,000 

90 

1  + 

3800 

In  none  of  these  cases  were  nucleated  reds  found,  but  the  films,  even 
that  of  case  (3),  were  exactly  like  those  of  a  mild  pernicious  anaemia  in 
other  respects,  showing  anisocytosis  and  poikilocytosis,  fairly  numerous 
megalocytes,  polychromasia,  and  in  (1)  and  (2)  some  granular  basophilia 


DISEASES   OF   THE   ALIMENTAEY   SYSTEM  305 

also.  Lymphocytes  were  relatively  in  excess.  Cases  (1)  and  (2) 
recovered;  (3)  died  suddenly  of  heart  failure  a  few  days  after  we 
saw   him. 

Intestinal  Pakasites 

Eosinophilia  is  the  striking  feature  of  these  infections,  but  is  not 
constant.  Speaking  generally,  our  experience  is  that  it  is  found  in 
cases  where  the  parasites  are  giving  rise  to  symptoms,  presumably  by 
their  toxins,  and  is  absent  when  they  are  not. 

Nematodes. — Oxyuris  Vermicularis. — There  may  be  slight  ansemia. 
Eosinophilia  is  inconstant.  Boycott1  found  a  definite  increase  of 
eosinophils  in  two-fifths  of  his  cases.  Bucklers 2  has  reported  eosino- 
philia reaching  16  per  cent. 

Ascaris  Lumbricoides. — Blood  changes  are  uncommon.  Eosinophilia 
may  occur.     Bucklers  records  a  count  of  19  per  cent. 

Ankylostoma  Duodenale. — Only  a  small  proportion  of  infected 
persons  exhibit  symptoms.  When  symptoms  do  occur  the  chief  feature 
is  anaemia.  The  degree  of  anaemia  recorded  by  different  authors  varies 
considerably.  This  seems  to  indicate  that  there  are  degrees  of  severity 
among  different  outbreaks  in  different  parts  of  the  world.  Boycott3 
regards  the  anaemia  not  as  a  true  reduction  of  the  number  of  red 
corpuscles  but  as  a  hydraemic  plethora,  a  condition  which  Lorrain 
Smith  holds  to  be  the  essential  change  in  chlorosis.  The  average 
size  of  the  cells  is  small,  the  colour  index  is  low,  anisocytosis  is  only 
moderate,  normoblasts  are  infrequent,  and  megaloblasts  rare.  Accord- 
ing to  American  authors  the  anaemia  seems  to  be  more  severe  in 
infections  both  with  the  old-world  hook  worm  and  its  American 
congener.  Ked  cells  may  fall  below  one  million,  and  polychromasia 
may  be  marked.  Poikilocytosis  may  be  present,  and  normoblasts  have 
been  frequently  noted.  Boycott  thinks  that  the  poverty  of  the  blood 
in  haemoglobin  is  proportionate  to  the  number  of  worms.  Leucocytosis 
is  commonly  present,  especially  in  early  infections,  but  when  anaemia 
has  supervened  the  leucocyte  count  may  be  diminished. 

In  nine-tenths  at  least  of  the  cases  there  is  eosinophilia.  The  per- 
centage of  these  cells  is  commonly  about  14,  but  much  higher  figures 
have  been  recorded.      Lichtenstern  found  72  per  cent,  in  one  case. 

1  Brit.  Med.  Journ.,  1903. 

2  Munch,  mecl.  Wochenschr.,  1894. 

3  Lancet,  18th  March  1911. 

20 


306  DISEASES   OF   THE   ALIMENTAKY   SYSTEM 

Boycott  found  the  onset  of  eosinophilia  after  infection  in  two  cases  to 
be  fourteen  and  twenty  days  respectively.  When  there  is  very  severe 
anaemia  the  eosinophilia  may  fail. 

Trichocephalus  Dispar. — Infection  is  not  associated  with  any  blood 
change. 

Trichina  Spiralis. — When  the  muscles  become  invaded  by  the 
embryonic  forms,  leucocytosis  is  the  rule.  The  increase  is  partly  due 
to  neutrophils,  but  eosinophilia  is  a  very  marked  feature — 60  per  cent, 
has  been  recorded.  This  is,  of  course,  of  much  importance  in  the 
diagnosis  from  enteric  and  similar  conditions. 

Cestodes. — In  occasional  cases  of  infection  by  tcenia  solium  and 
mediocanellata  there  is  anaemia.  Eosinophilia  and  sometimes  basophilia 
may  be  present. 

Bothriocephalus  Latus. — In  some  cases  anaemia  with  features  iden- 
tical with  those  of  pernicious  anaemia  may  occur.  It  is  said  that  this 
does  not  occur  so  long  as  the  parasite  is  healthy,  but  that  when  it  is 
diseased,  or  has  died  without  being  expelled,  toxins  are  produced  which 
give  rise  to  the  anaemia.  The  expulsion  of  the  worm  is  followed  by 
improvement  or  cure  of  the  anaemia. 

Taenia  Echinococcus. — When  the  cystic  stage  affects  man,  a  marked 
eosinophilia  is  the  rule.  Exceptions  are  common  in  our  experience. 
Welsh  and  Barling1  found  eosinophilia  in  three-fourths  of  their  cases, 
neutrophil  leucocytosis  exceeding  10,000  in  10  per  cent,  of  cases,  and 
a  slight  basophilia  in  15  per  cent. 

Diseases  of  the  Liver 

Catarrhal  Jaundice. — The  serum  is  stained  with  bile.  The  bile 
salts  are  strongly  haemolytic,  and  this  may  account  for  the  somewhat 
increased  size  of  the  red  cells  which  is  seen  in  cases  of  moderate 
severity.  In  mild  cases  the  blood  changes  are  practically  nil.  There 
is  no  leucocytosis. 

Cholsemia. — In  jaundice  of  long-standing,  anaemia  supervenes  and 
may  become  fairly  severe.  Haemoglobin  is  reduced  to  at  least  as  great 
an  extent  as  the  red  cells.  The  fragility  of  the  red  corpuscles  tends 
to  be  diminished.  In  severe  cases  there  may  be  some  slight  degree  of 
leucocytosis. 

1  Scot.  Med.  Journ.,  January  1907. 


DISEASES   OF   THE   ALIMENTAEY   SYSTEM  307 

Gall-Stones. — The  condition  of  the  blood  will  fall  into  the  condition 
described  in  one  or  other  of  the  paragraphs  immediately  above  where 
there  is  no  inflammation.  In  cases  where  the  passage  of  the  gall-stone, 
or  its  entry  into  the  common  duct  as  a  ball-valve,  is  attended  with 
rigor  and  rise  of  temperature,  there  is  a  moderate  leucocytosis,  with 
a  high  percentage  of  polymorphs,  and  sometimes  a  definite  glycogen 
reaction.  In  the  ball-valve  cases  the  local  pain  may  be  slight,  the 
jaundice  trivial,  and  they  are  apt  to  be  mistaken  for  malaria.  The 
leucocyte  count  should  prevent  this  error. 

Cirrhosis. — There  is  no  essential  change  apart  from  that  due  to 
jaundice  until  nutrition  is  affected.  Increasing  anaemia  of  secondary 
type  then  supervenes.  The  white  cell  shows  no  marked  change.  Their 
numbers  may  be  low,  due  to  malnutrition,  or  may  from  time  to  time 
be  increased,  due  to  toxaemia,  more  particularly  in  the  hypertrophic 
variety,  and  are  increased  after  haematemesis  or  meltena.  Eogers x 
in  a  series  of  Indian  cases  found  a  high  leucocyte  count  to  be  an 
unfavourable  sign. 

Acute  Yellow  Atrophy. — This  is  not  associated  with  anaemia, 
but  there  is  a  constant  leucocytosis,  of  moderate  amount — 15,000  to 
21,000. 

Abscess  of  the  Liver. — The  red  cells  are  not  affected  at  first.  In 
chronic  cases  there  may  be  severe  anaemia.  There  is  generally  leuco- 
cytosis. This  is  absolute  in  acute  cases,  but  may  be  only  relative  in 
chronic  cases  with  anaemia  (Eogers).  In  acute  hepatitis  without  abscess 
leucocytosis  is  nearly  always  absent,  and  may  disappear  towards  the 
fatal  termination  of  acute  cases.  There  is  said  to  be  a  very  marked 
glycogen  reaction  in  all  cases,  and  the  intensity  of  the  reaction  is  an 
indication  of  the  severity  of  the  condition.  The  blood  may  give 
important  indications  in  the  diagnosis  between  this  condition  and 
malaria. 

Diseases  of  the  Panceeas 

In  acute  pancreatitis  there  is   usually  a  well-marked  leucocytosis. 
In  chronic  pancreatitis  leucope  nia  is  the  rule. 
1  Lancet,  10th  August  1912. 


308  DISEASES   OF  THE  ALIMENTAKY  SYSTEM 

Peritonitis  and  Ascites 

Peritonitis  and  Tabes  Mesenterica. — See  Inflammation  and 
Tuberculosis. 

Ascites. — The  blood  changes  depend  on  the  causal  condition.  The 
ascites  may  per  se  have  some  effect.  Thus  ascites  which  is  causing 
cardiac  embarrassment  may  thereby  give  rise  to  artificially  increased 
counts  accompanying  cyanosis.  After  tapping  there  may  be  a  fall  due 
to  removal  of  cyanosis,  but  where  cyanosis  has  not  been  a  marked 
feature  the  counts  may  be  increased  after  tapping  from  a  rapid  refilling 
of  the  abdomen  with  serum. 


CHAPTER  XXXIV 

DISEASES  OF  THE  DUCTLESS  GLANDS 

Spleen. — The  great  majority  of  the  affections  of  the  spleen  are  due 
to  disease  elsewhere,  and  there  are  very  few  primary  diseases  of  the 
spleen  in  which  the  blood  is  affected. 

Enlargement  of  the  spleen  may  be  due  to  the  following  causes : — 

1.  Infections,  syphilis,  tuberculosis,  malaria,  kala-azar,  echinococcus, 
and  the  schistosoma  of  Japan. 

2.  Chronic  intestinal  affections  in  children,  cirrhosis  of  the  liver, 
acholuric  icterus. 

3.  Pernicious  anaemia,  chlorosis,  leukaemia,  lymphadenoma,  splenic 
anaemia,  Gaucher's  disease,  splenic  anaemia  of  infants,  haemochromatosis, 
splenomegalic  polycythaemia. 

4.  Heart  disease. 

5.  Waxy  disease,  sarcoma,  rickets,  wandering  spleen. 
Splenectomy. — A  considerable  number  of  cases  have  accumulated  in 

which  blood-counts  have  been  carried  out  for  prolonged  periods  after  the 
operation.  In  most  of  these  there  has  been  transient  enlargement  of 
lymphatic  glands,  appearing  any  time  up  to  eighteen  months  after 
operation.  Eosinophilia  (3  to  5  per  cent,  in  persons  whose  previous 
numbers  had  been  0*5  or  1)  may  occur  and  persist  for  weeks  or  months. 
There  is  usually  a  slight  lymphocytosis,  which  appears  to  be  permanent 
as  far  as  present  observations  go. 

Lymphatic  Glands. — Many  of  the  affections  of  the  lymphatic  glands 
are  not  peculiar  to  these  structures,  although  in  some  cases  they  may  be 
the  parts  primarily  attacked.  Some  gland  affections  are  secondary  to 
pathological  conditions  elsewhere.  The  blood  changes  are  described  in 
connection  with  the  etiological  or  primary  condition. 

Myxcedema. — There  is  practically  always  anaemia,  but  its  degree 
varies  greatly.  In  slight  cases  the  red  corpuscles  do  not  fall  below 
4,000,000  per  c.mm.,  but  in  more  advanced  instances  the  number  may 
be  a  million  less.     White  cells  are  usually  slightly  diminished  in  number. 


310  DISEASES   OF   THE   DUCTLESS   GLANDS 

There  is  a  relative  lymphocytosis.  The  percentage  of  lymphocytes  often 
exceeds  40.  In  several  cases  eosinophilia  has  been  present,  counts  of 
from  4  to  10  per  cent,  having  been  recorded. 

Cretinism. — Allowing  for  the  peculiarities  of  the  blood  in  children 
the  changes  are  similar  to  those  in  myxoedema. 

Exophthalmic  Goitre. — Apart  from  those  cases  which  are  associated 
with  chlorosis  there  is  a  certain  amount  of  mild  anaemia  in  about  50  per 
cent,  of  cases.  The  white  cells  may  show  no  change,  but  in  at  least  50 
per  cent,  of  cases  there  is  a  very  definite  lymphocytosis,  which  may 
reach  60  per  cent,  in  the  differential  count,  while  the  average  leucocyte 
count  is  increased  to  about  11,000.  We  have  met  with  two  cases  followed 
by  pernicious  ansemia.  One  was  a  female,  aged  45,  who  had  suffered 
from  exophthalmic  goitre  for  twenty  years.  She  had  several  attacks 
of  ansemia  from  which  she  recovered.  Most  of  the  goitre  symptoms 
disappeared,  but  eventually  her  red  cell  count  fell  to  1,150,000,  haemo- 
globin to  25  per  cent.,  leucocytes  to  1700,  and  the  blood-picture  was 
characteristic  of  pernicious  anaemia.  The  other  case,  a  female,  aged  25, 
suffered  from  exophthalmic  goitre.  By  the  age  of  30  the  symptoms  had 
given  place  to  those  of  myxoedema.  Soon  afterwards  pernicious  anaemia 
with  a  red  cell  count  of  1,500,000  supervened.  This  was  followed  by  a 
short  remission  (red  corpuscles  3,160,000,  Hb  82),  then  a  fatal  relapse. 

Acromegaly. — In  a  case  in  a  young  subject  with  giantism  Sabrazes 
and  Bonnes  found  a  very  slight  degree  of  anaemia,  a  slight  total  increase 
of  white  cells  (11,780),  with  a  marked  lymphocytosis  (49  per  cent.) ; 
while  in  an  adult  case  without  giantism  there  was  a  slight  increase  of 
red  cells  and  haemoglobin,  a  considerable  reduction  in  the  number  of 
white  cells,  chiefly  affecting  the  polymorphs,  so  that  the  most  striking 
feature  was  a  relative  lymphocytosis.  Dickson  found  slight  basophilia 
(up  to  2  per  cent.)  in  four  cases.  In  a  case  recently  under  our  care  the 
counts  were — reds,  4,900,000 ;  haemoglobin,  85  per  cent. ;  whites,  6800 ; 
with  the  proportions — polymorphs,  49  per  cent.;  lymphocytes,  48; 
eosinophils,  2  ;  basophils,  1  per  cent. 

Addison's  Disease. — There  is  generally  some  reduction  in  the  number 
of  red  corpuscles,  and  the  average  count  ranges  from  2>\  to  4§  millions,  but 
it  is  not  unusual  to  meet  with  cases  showing  anaemia  of  greater  severity. 
In  such  cases  some  polychromasia  and  a  few  nucleated  red  cells  may 


DISEASES   OF   THE   DUCTLESS   GLANDS  311 

be  found.  Hsemoglobin  shows  a  reduction  rather  greater  than  the 
corresponding  reduction  of  red  corpuscles.  It  has  been  stated  that 
methamioglobin  may  be  present  in  the  blood  in  advanced  cases.  In  a 
few  instances  an  increase  of  red  corpuscles  has  been  found.  "We  have 
only  once  met  this.  The  patient,  who  had  been  living  at  a  high  altitude 
in  Switzerland  in  search  of  health,  had  a  count  of  7,000,000,  Hb  110. 
The  count  dropped  to  normal  two  weeks  after  his  return  to  this  country. 
The  white  cells  are  rarely  increased  in  number.  More  frequently  there 
is  a  slight  diminution,  chiefly  affecting  the  polymorphs,  so  that  a  relative 
lymphocytosis  is  the  usual  finding.  The  number  of  eosinophils  is  usually 
increased.  Percentages  of  6  and  8  are  not  uncommon,  and  we  have 
met  with  a  case  showing  10  per  cent. 


CHAPTER  XXXV 

DISEASES   OF  THE   CIRCULATORY  AND   RESPIRATORY 

SYSTEMS 

Diseases  of  the  Circulatory  System 

Simple  Endocarditis. — The  blood  changes  vary  with  the  cause.     In  the 
rheumatic  cases  there  may  be  a  leucocytosis  of  some  intensity. 

Malignant  Endocarditis. — The  blood  changes  are  profound.  They 
consist  of  the  results  of  the  toxsemic  process  which  have  been  described  in 
Chapter  XXXI.,  associated,  it  may  be,  with  changes  due  to  the  mechanical 
interference  with  the  circulation  brought  about  by  incompetent  valves 
or  stenosis. 

Chronic  Endocarditis. — In  this  condition,  described  by  Osier  and 
Horder,  there  is  a  slowly  progressive  anaemia,  without  leucocytosis,  but,  as 
far  as  we  are  able  to  judge  from  the  cases  we  have  seen,  with  an  increased 
proportion  of  polymorphs.  Organisms  are  constantly  found  in  the  blood, 
usually  streptococci  of  attenuated  virulence,  but  the  glycogen  reaction 
is  negative,  as  one  would  expect  from  the  character  of  the  infection. 

Congenital  Heart  Disease. — High  blood-counts  are  common.  The 
red  cells  may  number  eight  millions  or  more.  The  white  cells  are  usually 
increased,  but  not  to  a  corresponding  extent.  The  hsemoglobin  per- 
centage is  raised  but  the  colour  index  is  usually  below  unity,  and  the 
red  corpuscles  are  often  small,  but  rarely  show  much  poikilocytosis.  A 
count  of  eight  millions  would  probably  be  associated  with  a  hsemoglobin 
percentage  of  120  or  130  instead  of  160.  The  increase  seems  to  be 
partly  a  compensatory  process  involving  increased  activity  in  blood 
formation  and  partly  due  to  cyanosis  and  stasis. 

Acquired  Heart  Disease. — Some  high  red  counts  have  been  recorded. 
The  number  of  red  corpuscles  is  not  usually  raised  in  fully  compensated 
valvular  disease,  nor  in  aortic  regurgitation  with  failure  of  compensation, 


CIECULATOEY  AND   EESPIEATOEY   SYSTEMS        313 

but  it  is  usually  above  the  normal  in  mitral  disease  when  compensation 
has  failed,  and  in  many  conditions  of  dilatation  and  chronic  strain 
(emphysema,  chronic  bronchitis)  without  valvular  disease,  in  which  the 
compensation  is  inadequate. 

Diseases  of  the  Eespiratory  System 

Adenoids. — There  is  practically  always  a  certain  degree  of  anaemia, 
characterised  by  diminished  haemoglobin  rather  than  oligocythemia. 
There  is  usually  also  some  increase  in  the  number  of  leucocytes,  and  the 
percentage  of  lymphocytes  is  commonly  increased,  as  in  all  enlargements 
of  lymphoid  tissue  in  childhood. 

Acute  Bronchitis. — Leucocytosis  occurs  with  some  frequency  but  is 
not  the  rule.  In  those  cases  where  the  smaller  tubes  are  involved  and 
the  question  of  possible  pneumonia  arises  there  is  apt  to  be  leucocytosis, 
so  that  the  leucocyte  count  alone  is  not  of  great  value  in  the  diagnosis. 
The  blood  examination  in  other  respects  may,  however,  give  important 
information  (see  Pneumonia). 

Chronic  Bronchitis. — In  most  cases  the  blood-picture  is  not  disturbed. 
Occasionally,  however,  one  meets  with  a  case  showing  some  increase  of 
white  cells.  The  explanation  would  appear  to  be  that  in  these  cases 
there  is  retention  of  secretion  leading  to  absorption  of  septic  products. 

Asthma. — In  a  certain  proportion  of  cases  of  true  spasmodic  asthma 
there  is  a  great  increase  of  eosinophil  cells  in  the  sputum  and  a 
definite  increase  of  eosinophil  cells  in  the  blood.  The  eosinophilia 
appears  a  few  hours  before  an  isolated  paroxysm  and  disappears 
rapidly  after  it,  but  in  cases  which  are  more  continuous  it  may  persist. 
The  eosinophilia  leads  to  a  slight  increase  in  the  total  count,  and  in 
a  few  cases  it  is  accompanied  by  a  moderate  neutrophil  leucocytosis. 
Little  is  known  as  to  the  explanation  of  the  presence  of  eosinophilia 
in  some  cases  and  not  in  others.  It  does  not  occur  in  cardiac  or  renal 
asthma,  or  necessarily  in  those  cases  due  to  bronchitis  or  to  latent 
tuberculous  mischief  in  the  lungs.  It  is  almost  always  present  in  cases 
associated  with  nasal  polypi,  and  the  polypi  themselves,  and  even  the 
nasal  secretion,  may  contain  large  numbers  of  eosinophils,  but  it  is  also 
found  in  cases  with  other  nasal  defects,  such  as  ceclema  of  the  lower 
turbinates.  Generally  speaking,  eosinophilic  asthmas  are  those  most 
likely  to  be  benefited  by  treatment  of  the  nasal  passages. 


314        CIRCULATORY  AND   RESPIRATORY   SYSTEMS 

Emphysema. — Just  as  in  cases  of  cardiac  failure,  there  may  he  an 
increase  of  blood-cells  due  to  peripheral  stasis  in  cases  with  cardiac 
dilatation.  Eigers 1  found  an  increased  volume  of  cells  in  proportion 
to  plasma.  This  may  be  due  to  an  increased  number  of  red  cells,  but 
in  some  cases,  especially  in  old  people,  he  found  that  the  volume  of  the 
individual  red  cells  was  increased.  Eosinophilia  has  been  noticed  in  a 
few  cases,  probably  where  the  emphysema  is  secondary  to  asthma. 

Bronchiectasis  and  Abscess  of  the  Lung. — There  is  anaemia  corre- 
sponding to  the  duration  and  severity  of  the  affection,  and  an  increase 
of  white  cells  varying  with  the  severity  of  the  infection  and  the  amount 
of  absorption.  As  the  blood  changes  in  phthisis  at  a  stage  likely  to  be 
confused  with  these  conditions  are  also  due  to  sepsis,  the  blood  does 
not  help  in  the  differential  diagnosis.  The  glycogen  reaction  may  be 
present,  especially  in  cases  where  the  discharge  of  pus  is  not  free. 

Phthisis. — See  Tuberculosis. 

Pneumonia. — The  blood  shows  changes  of  very  great  diagnostic  and 
prognostic  importance.  A  very  striking  change  is  the  rapidity  of  coagu- 
lation time  and  the  abundance  of  the  fibrin  network. 

Ewart  in  a  study  of  this  subject  (Edinburgh  thesis,  unpublished) 
found  that  there  is  a  gradual  shortening  of  the  coagulation  time  up  till 
the  crisis,  sometimes  more  abrupt  just  before  it.  After  the  crisis  the 
coagulation  time  gradually  returns  to  the  normal  for  the  individual. 
In  cases  subsiding  by  lysis  the  return  of  the  coagulation  time  to  normal 
is  much  more  gradual.  The  coagulation  time  is  not  affected  by  varia- 
tions in  the  temperature,  by  the  actual  number  of  leucocytes,  or  by  the 
percentage  of  polymorphs.  Ewart  suggests  a  parallelism  between  the 
number  of  degenerated  leucocytes  and  the  coagulation  time.  He  found 
that  a  coagulation  time  of  less  then  one  minute  always  betokened  a 
fatal  result. 

In  cases  followed  by  empyema  there  is  a  lengthening  of  coagulation 
time  after  the  crisis,  followed  by  a  second  period  of  shortening  during 
the  acute  stage  of  the  empyema.  The  red  cells  may  show  an  increase 
due  to  accumulation  at  the  periphery  in  cases  with  cyanosis.  The 
haemoglobin  and  the  specific  gravity  are  correspondingly  increased. 
There  may  be  slight,  anaemia  after  the  crisis. 

White  Cells. — The  rule  is  an  increased  number  of  leucocytes.  This 
1  Eiger,  Folia  Hcematologica,  vii.  1909,  233. 


CIECULATOEY  AND   BESPIRATOEY   SYSTEMS        315 

increase  does  not  correspond  either  to  the  temperature  or  the  amount 
of  lung  involved,  but  is  rather  the  expression  of  the  resistance  of  the 
patient  to  the  toxin.  While  the  phenomenon  is  of  diagnostic  import- 
ance, it  is  probable  that  it  has  even  more  value  as  a  prognostic  guide. 
Cases  with  slight  symptoms  may  have  no  increase  of  white  cells, 
but  this  very  rarely  occurs.  In  such  cases  there  is  usually  a  slight 
leucocytosis.  On  the  other  hand,  cases  with  very  severe  symptoms  may 
show  no  increase  or  more  often  a  diminution  of  leucocytes.  These  are 
cases  in  which  the  tissues,  including  the  bone-marrow,  are  overwhelmed 
by  the  toxin  before  they  can  react,  and  they  are  invariably  fatal.  In 
the  great  majority  of  cases  there  is  an  increase  of  white  cells,  ranging 
from  11,000  to  50,000  per  c.mm.  Our  highest  count  has  been  65,000, 
but  a  count  of  100,000  has  been  recorded.  Leucocytosis  is  generally 
found  when  cases  first  come  under  observation,  so  that  it  is  probably 
present  from  the  commencement  of  the  illness.  We  have  found  it 
present  within  three  hours  from  the  initial  rigor.  There  is  little 
variation  throughout  the  disease  till  a  day  or  so  before  the  crisis ;  the 
count  then  shows  a  tendency  to  fall  in  the  favourable  cases,  but  in  some 
fatal  cases  the  same  thing  is  found.  Although  the  leucocytes  may  have 
begun  to  diminish  before  the  fall  of  temperature,  they  do  not  reach 
their  normal  number  for  several  days  after  the  crisis,  and  in  cases  ending 
by  lysis  their  fall  may  be  very  gradual.  When  the  leucocytes  fall  in 
number  about  the  time  of  the  crisis  but  fail  to  return  to  their  normal 
number  within  three  or  four  days  we  have  an  almost  certain  indication 
of  some  complication  such  as  empyema,  toxic  nephritis,  or  pericarditis. 

Differential  Counts. — Up  to  the  crisis  there  is  an  increase  of  poly- 
morphs, which  may  constitute  95  per  cent,  of  the  white  cells.  A  few 
myelocytes  are  almost  invariably  present  in  severe  cases.  Transitional 
cells  and  large  lymphocytes  are  also  increased  absolutely  though  the 
percentage  may  be  low.  Small  lymphocytes  and  eosinophils,  on  the 
other  hand,  are  absolutely  and  relatively  diminished.  The  latter  may 
disappear  altogether.  After  the  crisis  the  polymorphs  diminish  while 
the  large  lymphocytes  maintain  their  numbers  for  a  day  or  two.  The 
small  lymphocytes  and  the  eosinophils  are  gradually  restored  to  their 
normal  numbers.  The  persistence  of  eosinophils  or  their  return  before 
the  crisis  is  a  favourable  element  in  prognosis.  In  the  severe  cases 
with  a  low  leucocyte  count  the  proportional  relations  between  poly- 
morphs and  lymphocytes  may  remain  unchanged,  the  polymorphs  may 
be  diminished  or  increased. 

Leucolysis. — In  no  other   disease,  with   the   possible    exception   of 


316         CIRCULATOEY  AND   RESPIRATORY  SYSTEMS 

cancerous  cachexia,  is  there  so  great  a  destruction  of  leucocytes  in  the 
blood.  The  degenerative  changes  may  consist  merely  of  vacuolation  of 
the  protoplasm.  Both  polymorphs  and  large  lymphocytes  are  affected 
in  this  way.  The  more  intense  changes  chiefly  affect  the  polymorphs. 
The  granules  of  the  affected  cells  are  less  distinctly  stained,  and  there 
may  be  considerable  fraying  or  even  disintegration  of  the  protoplasm, 
while  all  degrees  of  karyolysis  may  be  traced  in  different  cells.  These 
changes  are  more  marked  in  the  more  severe  cases. 

Glycogen  Reaction. — This  is  always  present.  It  can  be  made  out 
when  cases  first  come  under  observation,  but  becomes  rather  more 
intense  and  affects  a  larger  number  of  cells  a  day  or  two  before  the 
crisis.  After  the  crisis  the  reaction  remains  for  a  few  days  and  may 
be  distinctly  present  after  the  leucocyte  count  has  returned  to  normal. 
In  the  severe  leucopenia  cases  the  glycogen  reaction  is  always  intense, 
but  if  the  polymorphs  are  diminished  of  course  relatively  few  cells  will 
show  the  change. 

Blood-Plates. — The  plates  are  always  diminished  in  the  blood  up  to 
the  time  of  the  crisis.  After  the  crisis  they  are  more  abundant  than 
usual. 

Bacteria. — The  diplococcus  lanceolatus  has  repeatedly  been  cultivated 
from  the  blood.  Those  observers  who  have  made  cultures  in  a  series 
of  cases  have  found  the  cocci  most  frequently  in  severe  cases  or  cases 
with  general  infection,  so  that  the  finding  of  organisms  in  any  case  may 
be  regarded  as  a  serious  prognostic  indication. 

Significance  of  the  Blood  Changes  in  Pneumonia — Diagnosis. — The 
most  important  features  are  the  decreased  coagulation  time,  the  leuco- 
cytosis,  and  the  glycogen  reaction.  The  diminished  coagulation  time 
would  almost  alone  serve  to  distinguish  pneumonia  from  any  of  the 
fevers  with  which  it  is  the  least  likely  to  be  confounded.  In  most 
cases  the  leucocyte  count  is  greater  than  the  initial  counts  of  either 
tubercular  meningitis  or  typhoid  fever,  and  in  neither  of  these  condi- 
tions is  a  glycogen  reaction  to  be  found  at  the  outset.  The  coagulation 
time  and  the  glycogen  reaction  will  help  to  distinguish  pneumonia  from 
bronchitis  affecting  the  smaller  tubes.  In  cases  of  acute  pleurisy  there 
may  be  a  considerable  leucocytosis,  and  in  the  rheumatic  cases  there 
may  be  considerable  acceleration  of  the  coagulation  time,  but  the 
glycogen  reaction  is  absent. 

Prognosis. — Most  help  is  obtained  from  the  coagulation  time,  the 
total  and  the  differential  leucocyte  counts,  and  the  glycogen  reaction, 
and  especially  in  the  relation  of  the  last  three  factors  to  one  another. 


CIECULATOEY  AND   EESPIEATOEY  SYSTEMS        317 

The  coagulation  time  is  of  great  importance.  The  more  the  time  is 
accelerated  the  more  grave  is  the  prognosis.  This  will  readily  be  under- 
stood when  it  is  borne  in  mind  that  ante-mortem  clotting  is  almost 
invariably  found  on  post-mortem  examination  of  cases  of  pneumonia. 
The  leucocyte  count  is  of  very  great  importance.  Severe  cases  with  no 
increase  or  a  diminution  are  doomed.  It  may  be  said  that  more  cases 
die  with  under  13,000  leucocytes  per  c.mm.  than  with  larger  counts.  In 
those  cases  with  marked  leucocytosis  the  actual  numbers  do  not  afford 
much  information,  except  that  high  counts  usually  mean  a  severe  case, 
but  with  good  resisting  power.  When  the  usual  fall  after  the  crisis  is 
interrupted  a  complication  is  practically  certain.  Provided  that  there 
is  a  sufficiently  large  total  count,  the  percentage  of  polymorphs  is  not 
a  matter  of  great  importance,  except  that  it  is  highest  in  the  severer 
cases.  The  early  appearance  of  myelocytes  or  of  degenerated  forms  is 
a  serious  indication.  The  early  absence  of  eosinophils  indicates  a  severe 
case ;  their  early  return  is  one  of  the  most  favourable  indications.  The 
most  favourable  cases  are  those  with  a  slight  leucocytosis,  say,  15,000 
to  20,000,  with  a  polymorph  proportion  not  exceeding  80  per  cent.,  and 
with  a  slight  glycogen  reaction.  Of  two  cases  with  a  count  of  25,000 
the  more  favourable  is  that  with  the  lower  polymorph  percentage  and 
the  less  marked  glycogen  reaction. 


CHAPTER   XXXVI 

DISEASES  OF  THE  SKIN,  GENITO-URINARY  AND  NERVOUS 
SYSTEMS— GENERAL  DISEASES 

Diseases  of  the  Skin 

A  small  number  of  diseases  of  the  skin  affect  the  blood,  but  in  most 
of  them  the  changes  are  very  inconstant  in  their  incidence  and  degree. 
In  all  skin  diseases  associated  with  much  inflammation  or  ulceration 
a  moderate  leucocytosis  may  be  expected,  and  in  almost  all  chronic  cases 
there  is  a  slight  eosinophilia  of  about  4  per  cent. 

Erythema. — A  slight  polymorph  leucocytosis  may  be  found.  This 
is  perhaps  most  constant  in  febrile  cases  of  erythema  nodosum. 

Pemphigus. — Eosinophilia  seems  to  be  the  rule  in  all  varieties,  and 
polymorph  leucocytosis  is  almost  constant.  In  P.  foliaceus  from  8  to 
30  per  cent,  of  eosinophils  have  been  found,  and  in  P.  vegetans  15  per 
cent,  has  been  recorded. 

Dermatitis  Herpetiformis. — Eosinophilia,  sometimes  intense,  reach- 
ing 45  per  cent,  in  some  of  our  cases,  is  practically  constant  during  the 
recurrent  attacks,  but  usually  disappears  in  the  intervals.  Eosinophils 
are  found  in  large  numbers  in  the  vesicles  before  they  break,  but 
thereafter  are  often  replaced  by  polymorphs. 

Psoriasis. — In  a  few  cases  leucocytosis  has  been  noted.  The  records 
of  differential  counts  vary  very  greatly. 

Lupus. — In  tuberculous  lupus  anaemia  is  uncommon.  In  some 
ulcerative  cases  there  has  been  a  slight  polymorph  leucocytosis,  in  a 
few  cases  a  slight  lymphocytosis  either  relative  or  absolute  as  in 
other  tuberculous  infections,  but  in  the  majority  of  cases  the  blood 
is  unchanged. 


DISEASES   OF  THE   UEINAEY   SYSTEM  319 

Pellagra. — In  several  cases  there  has  been  a  slight  increase  of  white 
cells  with  a  high  percentage  of  lymphocytes.  A  slight  eosinophilia  has 
also  been  found. 

Mycosis  Fungoides. — Slight  anaemia  with  leucopenia,  eosinophilia 
(4-8  per  cent.),  and  more  rarely  a  slight  increase  of  basophils  has 
been  noticed. 

Recklinghausen's  Disease. — Gaillard }  found  a  slight  eosinophilia 
in  a  small  proportion  of  cases. 


Diseases  of  the  Urinary  System 

Acute  Nephritis. — -A  moderate  degree  of  anaemia  is  usually  present, 
and  it  may  become  severe.  There  is  often  a  slight  polymorph  leuco- 
cytosis,  with  diminution  of  eosinophils  at  the  outset.  This  is  frequently 
noticed  in  nephritis  occurring  in  the  course  of  other  diseases,  e.g. 
scarlatina,  in  which  leucocytosis  may  precede  the  nephritis,  and  in 
pernicious  anaemia.  Slight  eosinophilia  has  been  found  to  accompany 
the  resolution  stage. 

Chronic  Parenchymatous  Nephritis. — Anaemia  tends  to  become 
severe  and  haemoglobin  to  be  greatly  diminished,  so  that  the  colour 
index  may  be  low.  The  leucocyte  count  varies  probably  according 
to  the  amount  of  uraemic  poisoning.  As  a  rule  the  white  cells  are 
diminished. 

Chronic  Interstitial  Nephritis. — There  is  not  the  same  tendency  to 
anaemia  that  exists  in  the  parenchymatous  variety,  nor  is  leucocytosis 
common.  In  cases  with  signs  of  cardiac  failure  there  may  be  increased 
counts  due  to  peripheral  stasis,  and  it  should  be  kept  in  mind  that 
haemorrhage  diminishes  the  red  cell  count  while  increasing  the 
leucocytes,  and  that  uraemia  may  lead  to  a  leucocytosis  of  some 
importance. 

Pyelitis. — As  in  other  septic  conditions,  there  is  anaemia  and  poly- 
morph leucocytosis.  There  are  certain  cases  in  which  temporary  blocking 
of  the  ureter  occurs,  caused  apparently  either  by  swelling  of  the  mucous 

1  Soc.  de  Biolog.,  lxi.  1906,  563. 


320         DISEASES   OF   THE  REPRODUCTIVE   SYSTEM 

membrane  or  by  masses  of  pus  or  debris.  Clinically  this  is  often 
revealed  by  rigors  and  by  a  temporary  diminution  of  the  amount  of 
pus  in  the  urine.  The  blood  always  shows  leukocytosis,  with  a  more  or 
less  marked  glycogen  reaction.  "When  the  block  ceases  the  leucocyte 
count  drops  and  the  glycogen  reaction  disappears.  We  have  several 
times  seen  this  condition  mistaken  for  malaria  in  people  who  had  lived 
in  tropical  countries. 

Renal  Calculus. — Any  blood  change  which  may  occur  will  depend 
on  haemorrhage  or  pyelitis. 

Cystitis. — There  may  be  anaemia.  Leucocytosis  is  usually  absent, 
as  there  is  no  retention  of  septic  products. 

Bilharziosis. — There  is  a  moderate  secondary  anaemia  in  most 
cases,  which  may  become  severe  in  cases  where  there  is  great  loss 
of  blood,  secondary  suppuration,  and  especially  if  there  is  chronic 
diarrhoea.  There  is  a  slight  increase  in  the  leucocyte  count,  eosino- 
phils and  large  lymphocytes  being  increased  and  polymorphs 
diminished,  at  least  relatively.  The  leucocytosis  corresponds  roughly 
in  amount  with  the  severity  of  the  condition. 

Diseases  of  the  Eepeoductive  System 

Ovarian  Cystoma. — In  simple  cysts  the  blood  is  not  affected;  in 
malignant  or  inflammatory  conditions  the  blood  follows  the  usual 
course  in  these  conditions. 

Septic  and  Inflammatory  Conditions. — The  blood  changes  follow 
the  usual  rales.  Leucocytosis  may  be  of  great  value  in  distinguishing 
septic  mischief  from  ectopic  gestation,  hydrosalpinx,  etc.  The  leuco- 
cyte count  after  operation  gives  a  guide  to  the  efficacy  of  drainage. 
In  cases  of  pelvic  exudation  a  high  or  increasing  leucocytosis  may 
indicate  the  presence  of  pus,  in  chronic  pelvic  abscess  the  leuco- 
cytes may  not  be  much  increased,  but  are  likely  to  show  the 
glycogen  reaction. 

Ectopic  Gestation. — There  may  be  a  moderate  leucocytosis.  There 
is,  however,  no  glycogen  reaction  and  no  increase  of  fibrin  or  increased 
coagulability.      After   haemorrhage   the   diminution   of   red  cells  may 


DISEASES   OF   THE   NERVOUS   SYSTEM  321 

indicate  the  diagnosis,  and  there  is  a  sudden  increase  of  leucocytes. 
The  anaemia  is  sometimes  grave  in  itself. 

Eclampsia. — Observations  are  very  scanty.  There  is  a  definite 
leucocytosis  as  a  rule,  and  the  behaviour  and  indications  given  by 
the  leucocyte  count  are  practically  the  same  as  in  septic  conditions. 

Myoma. — The  blood-picture  is  negative  in  the  absence  of  haemor- 
rhage, but  prolonged  menorrhagia  from  this  cause  may  give  rise  to 
very  severe  secondary  anaemia.  The  lowest  count  we  had  was  reds, 
2,600,000;  haemoglobin,  23  per  cent.;  whites,  6300,  with  a  considerable 
number  of  normoblasts.  At  the  end  of  a  month  of  treatment  with 
rest,  iron,  etc.,  the  reds  were  4,000,000,  haemoglobin  62  per  cent.  In 
such  cases  each  menstrual  flow  causes  a  marked  drop  in  reds  and. 
haemoglobin.  The  question  of  surgical  intervention  is  discussed 
on  page  173. 

Diseases  of  the  Nervous  System 

Peripheral  Neuritis. — The  red  cells  are  not  affected.  There  may 
be  some  increase  of  leucocytes  according  to  the  cause.  In  alcoholic 
multiple  neuritis  there  is  a  moderate  increase  of  white  cells  in  most 
cases,  with  an  increased,  percentage  of  polymorphs. 

Anterior  Poliomyelitis. — There  is  generally  a  moderate  leuco- 
cytosis during  invasion  in  cases  which  begin  acutely. 

Spinal  Scleroses. — In  these  diseases  the  blood  is  unaffected. 

Meningitis. — See  Septic  Conditions  and  Tuberculosis. 

Chorea. — Eed  cells  are  normal.  There  may  be  slight  leucocytosis. 
Eosinophilia  has  been  described,  and  this  observation  has  been  used 
as  an  argument  to  prove  that  chorea  is  not  associated  with  rheuma- 
tism, in  which  eosinophilia  does  not  occur.  For  some  years  we  have 
examined  the  blood  of  all  our  cases  of  chorea  but  have  not  found, 
eosinophilia  to  be  even  usual,  much  less  constant. 

Epilepsy. — Slight  anaemia,  chiefly  affecting  the  haemoglobin,  may 

be  present.      There  is  often  leucocytosis   (10,000    to   18,000)   in   the 

intervals,  and  this  greatly  increases   during  the   fits.      A   few  cases 

21 


322  GENERAL  DISEASES 

show  eosinophilia.  The  almost  constant  leucocytosis  has  been  used 
as  an  argument  in  favour  of  the  toxaemic  origin  of  the  disease,  and 
we  have  often  found  it  useful  in  diagnosis  in  cases  where  the  fits 
were  badly  described  or  doubtful  in  character. 

Cerebral  Haemorrhage. — A  moderate  leucocytosis  is  the  rule  in 
recent  cases. 

Cerebral  Tumour  and  Abscess. — The  changes  are  the  same  quali- 
tatively as  in  these  conditions  elsewhere,  but  are  usually  much  less 
intense. 

General  Paralysis  of  the  Insane. — There  is  a  moderate  and  pro- 
gressive anaemia,  involving  chiefly  a  diminution  of  the  haemoglobin. 
In  the  first  stage  there  is  a  polymorph  leucocytosis  which  may  show 
exacerbations  at  intervals.  In  the  second  stage  there  is  generally  a 
reduction  of  the  polymorphs  and  at  least  a  relative  increase  of  lympho- 
cytes, especially  of  the  large  forms.  The  polymorphs,  however,  are 
increased  at  intervals,  and  there  is  slight  eosinophilia  from  time  to 
time.  In  the  third  stage  the  polymorphs  diminish  considerably  and 
lymphocytes  show  a  corresponding  increase. 

During  convulsive  seizures  there  is  usually  a  sudden  and  great 
increase  of  polymorphs  and  a  smaller  increase  of  large  lymphocytes. 
Myelocytes  may  also  appear  in  considerable  numbers. 

Mania. — In  practically  all  forms  of  excited  insanity  there  is  a 
polymorph  leucocytosis,  which  increases  with  exacerbations.  In 
delirium  tremens  and  continuous  alcoholic  mania  there  is  leucocytosis. 
Puerperal  mania  often  shows  leucocytosis,  but  this  is  not  constant. 
Eosinophilia  (up  to  8  per  cent.)  is  not  uncommon. 

General  Diseases 

Diabetes  Mellitus. — In  early  cases  as  long  as  the  patient  is  in 
comparatively  good  health  the  number  of  red  cells  tends  to  be  rather 
high,  with  a  corresponding  increase  of  haemoglobin.  The  counts  are 
apt  to  be  disturbed  by  changes  in  osmosis  disturbing  the  balance 
between  blood  and  tissue  fluids.  In  cachetic  cases  there  is  anaemia. 
Certain  special  staining  reactions  in  the  red  cells  have  been  described ; l 

1  Bremer,  New  York  Med.  Journ.,  7th  March  1896.  Williamson,  Brit.  Med.  Journ., 
19th  September  1896. 


GENEEAL  DISEASES  323 

they  are  of  no  practical  value.  The  "extra-cellular"  glycogen  is 
increased.  The  white  cells  are  practically  unaffected  as  regards 
numbers.  Von  Limbeck  states  that  there  may  be  an  unusually 
large  digestion  leucocytosis.  In  diabetic  coma  red  cell  counts  may 
be  high  from  cyanosis.  The  glycogen  reaction  becomes  positive, 
and  there  is  usually  a  leucocytosis.  Lipsemia  has  already  been 
discussed  (p.  191). 

Acute  Rheumatism. — There  is  a  remarkable  increase  in  the  fibrin 
network,  but  the  coagulation  time  is  not  more  rapid  than  usual.  Eed 
cells  are  nearly  always  diminished,  but  rarely  fall  below  4,000,000. 
Haemoglobin  is  reduced.  White  cells  are  always  increased,  but  very 
rarely  reach  or  exceed  20,000.  12,000  to  15,000  is  the  usual  count 
in  uncomplicated  cases.  The  glycogen  reaction  is  absent,  a  point 
which  may  be  of  considerable  diagnostic  value.  Organisms  are  not 
usually  found. 

Chronic  Rheumatism. — The  blood  is  unchanged. 

Rheumatoid  Arthritis. — In  their  study  of  forty-two  cases  Bull- 
more  and  Waterhouse  found  a  slight  degree  of  anaemia  to  be  almost 
always  present.  Except  for  the  occasional  appearance  of  a  few 
myelocytes  the  white  cells  were  normal. 

Gout. — In  acute  attacks  fibrin  is  increased.  As  in  other  conditions 
in  which  there  is  an  excess  of  purins  (endogenous  or  exogenous)  in  the 
blood,  uric  acid  can  frequently  be  separated  from  the  serum  by  means 
of  the  thread  test.  Eed  cells  are  not  affected  except  in  long-standing 
and  severe  cases,  which  may  be  anaemic.  Leucocytes  are  usually 
unaffected,  but  may  be  slightly  increased  in  acute  attacks. 

Rickets. — Anaemia  is  frequently  associated  with  rickets,  but  should 
probably  be  regarded  as  a  consequence  of  the  common  cause  rather 
than  a  result  of  rickets  per  se.  In  a  recent  series  Finlay  found 
a  complete  absence  of  signs  of  anaemia  in  uncomplicated  cases,  but 
there  was  some  variation  in  the  size  of  the  red  cells.  Enormously 
large  leucocyte  counts  have  been  recorded,  but  these  are  to  be  regarded 
as  the  result  of  complications.  Having  due  regard  to  the  age  of  the 
patients,  it  is  difficult  to  say  that  the  leucocytes  show  any  abnormal 
features. 


324  GENEBAL  DISEASES 

Osteomalacia. — The  various  statements  regarding  changes  in  the 
reaction  of  the  blood  have  not  been  authenticated.  Pappenheim  and 
others  have  examined  the  cells  with  negative  results.  In  the  later 
stages  there  may  be  anaemia  and  leucocytosis,  both  very  slight. 
Eosinophilia  has  been  described,  and  in  a  case  under  our  care  the 
eosinophils  were  constantly  about  5  per  cent. 


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Figs.  1-10. — Tertian  Malarial  Parasites. 

1-6.  Trophozoites. 
1.  Schizont. 

S.  Macrogametocyte  or  female. 
'.».  M  ierogametocyte  or  male. 
10.  Segmenting  form. 


Figs.  11-15. — Quartan  Malarial  Parasites. 

11,  12.  Trophozoites. 

13.  Macrogametocyte. 

14.  Microgametocyte. 

15.  Segmenting  form. 


Figs.  16-23. — yEstivo-Autumnal  Parasites. 

16,  17.  Trophozoites. 

IS,  19.  Schizonts. 

20.  Flagellated  form. 

21.  Microgametocyte  or  male. 
22,  23.  Macrogametocyte  or  female. 

Fig.  24. — Trypanosoma  Gambiense. 

Fici.  25.-  ■Leisttman-Donovan  Bodies. 


A.  G.,  fecit. 


PAET   V 
DISEASES  DUE  TO  ANIMAL  PARASITES  IN  THE  BLOOD 

CHAPTER  XXXVII 

MALARIA   OR   AGUE 

Definition. — A  specific  febrile  disease  caused  by  the  introduction  into 
the  blood  of  protozoal  parasites  by  the  agency  of  mosquito  bites. 

Distribution. — Malaria  is  widely  distributed  throughout  the  world. 
It  is  found  throughout  Africa,  except  in  parts  of  Cape  Colony,  and 
throughout  Asia.  It  occurs  in  West  Australia  and  the  Polynesian 
Islands,  in  most  of  South  America,  parts  of  the  United  States,  and  in 
Canada  about  the  northern  shore  of  Lake  Ontario.  In  Europe  there  are 
probably  endemic  centres  in  all  the  countries  except  Great  Britain  and 
Norway.  The  distribution  may  vary  considerably  in  the  course  of  a  few 
years.  A  series  of  wet  seasons  may  greatly  extend  the  distribution  of 
the  disease,  and  dry  seasons  or  antimalarial  measures  may  curtail  it. 

Etiology. — Malaria  is  caused  by  the  parasites  Plasmodium  vivax, 
which  gives  rise  to  tertian  malaria ;  Plasmodium  malarias,  which  gives 
rise  to  quartan  fever ;  and  Laverania  malarias,  which  gives  rise  to  asstivo- 
autumnal  fever  or  subtertian  malaria.  The  parasites  are  introduced 
into  the  blood  by  the  bite  of  an  anopheline  mosquito.  Anopheles 
maculipennis  is  perhaps  the  most  common  cause  of  malaria  in  Europe, 
but  at  least  twenty  members  of  the  anopheles  family  are  known  carriers 
of  the  disease.  Only  the  female  mosquito  sucks  blood  and  transmits 
the  infection. 

Life-History  of  the  Parasite 

A.  In  Man — Schizogony. — In  the  cells  and  ducts  of  salivary  glands 
of  infected  insects  parasites  are  found  in  the  form  of  fusiform  bodies, 
measuring  about  15  x  1"5  p  (Fig.  15).  These  bodies  consist  of  cytoplasm 
with  a  chromatin  nucleus  and  are  known  as  sporozoites.     When  the 


326  MALAEIA   OK  AGUE 

mosquito  bites  man  he  is  inoculated  with  these  sporozoites,  which 
invade  the  red  blood  corpuscles  and  develop  into  small  parasites  called 
trophozoites.  These  trophozoites  (Plate  XV.,  1,  2,  3)  increase  in  size, 
and  by  the  formation  of  a  vacuole  become  ring-shaped.  They  throw 
out  pseudopodia  and  continue  to  grow,  producing  a  pigment  of  excre- 
mentitious  nature,  which  accumulates  in  the  form  of  granules.  "When 
fully  grown  the  trophozoite  loses  its  power  of  amoeboid  movement, 
becomes  spherical  and  full  of  pigment  granules.  It  is  now  known  as 
a  schizont.  The  parasite  next  breaks  up  into  segments,  each  contain- 
ing a  portion  of  nuclear  chromatin.  The  segments  or  spores  are 
known  as  merozoites.  A  residual  mass  containing  the  pigment  is  left 
unsegmented.  The  blood  corpuscle  now  breaks  up.  The  merozoites 
are  liberated  and  some  of  them,  as  well  as  the  residual  mass  and 
pigment,  are  taken  up  by  leucocytes  and  destroyed.  The  merozoites 
may  again  enter  blood  corpuscles  and  start  again  as  trophozoites, 
thus  completing  an  asexual  cycle — the  cycle  of  Golgi  (Fig.  27,  Cycle  a). 
The  repetition  of  this  process  leads  to  a  multiplication  of  the  parasites, 
and  each  rupture  of  a  corpuscle  allows  the  liberation  of  toxins,  so 
that  in  the  course  of  perhaps  eight  to  ten  or  twelve  days  (the  incuba- 
tion period)  the  collective  toxin  is  sufficient  to  determine  an  attack 
of  fever. 

The  earliest  form  of  sexual  parasite  is  like  an  ordinary  merozoite, 
but  it  grows  more  slowly,  never  develops  a  vacuole,  and  becomes  a 
crescent.  The  crescent  may  be  heavily  pigmented  and  granular  and 
is  distinguished  as  a  female  {meter ogametocyte,  female  sporont),  or  may 
be  lighter  and  clearer  and  is  then  differentiated  as  a  male  (micro- 
gametocyte,  male  sporont).  The  macrogametocytes  possess  a  small 
rounded  nucleus,  poor  in  chromatin  and  placed  eccentrically,  and  a 
granular  and  pigmented  cytoplasm  (Plate  XV.,  8).  They  are  tenacious 
of  life,  and  as  the  result  of  a  chill  or  diminished  health  in  their  host 
they  may  sporulate  and  the  merozoites  may  again  invade  fresh  blood 
corpuscles  (Fig.  27,  Cycle/).  This  would  account  for  attacks  of  malaria 
months  or  years  after  infection. 

A  different  view  is,  however,  held  by  Thomson,1  who  maintains  that 
crescents  die  in  the  peripheral  blood  in  a  few  days,  and  that  fresh  breeds 
come  into  the  circulating  blood  as  the  result  of  replenishment  from  surviving 
asexual  forms  in  the  internal  organs,  chiefly  the  hone-marrow  and  spleen. 
Thomson  also  holds  that  there  is  not  sufficient  evidence  to  support  the  view 
that  crescents  are  able  to  revert  back  to  the  asexual  phase. 

1  Annals  of  Troj).  Med.,  viii.  1914,  p.  85. 


MALARIA   OR   AGUE  327 

The  microgametocyte  is  characterised  by  a  large  nucleus,  extending 
like  a  band  across  the  protoplasm,  with  abundant  chromatin,  clear 
protoplasm,  and  less  pigment  than  the  female  (Plate  XV.,  9).  The 
macrogametocyte  and  microgametocyte  are  the  means  of  propagating 
the  parasite  in  the  mosquito,  and,  unlike  the  female  bodies,  if  the 
microgametocytes  fail  to  reach  the  intestine  of  the  mosquito  they  die 
off  (Fig.  27,  Cycle  m). 

It  has  been  customary  to  regard  the  malaria  parasite  as  intracorpus- 
cular.  Mary  Eowley-Lawson l  maintains  that  it  is  extracorpuscular  during 
its  entire  developmental  cycle.  The  parasite  attaches  itself  to  the  corpuscle 
by  means  of  thread-like  processes.  Other  pseudopodia  form  a  loop  on  the 
surface  of  the  corpuscle,  and  squeeze  up  the  portion  of  the  corpuscle  within 
the  loop  into  a  conical  mound.  When  viewed  from  the  surface  the  pseudo- 
podia give  the  characteristic  ring-form  appearance.  The  portion  of  corpuscle 
within  the  pseudopodia  loses  its  haemoglobin  and  gives  rise  to  the  "  achro- 
matic zone." 


«\ 

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Fig.  27.— Life-History  or  the  Malaria  Parasite. 

a.  The  asexual  cycle  in  man.  /.  the  female  cycle  in  man.  m.  The  male  cycle  in  man.  f1,  »', 
Female  and  male  gametes  which  conjugate  in  the  mosquito  to  form  a  zygote— the  ookinete.  This 
forms  an  oocyst,  different  stages  of  which  are  shown  under  the  epithelium  of  the  stomach  of 
the  mosquito.  Eventually  the  oocyst  develops  sporoblasts  which  become  sporozoites.  When 
the  cyst  raptures  these  reach  the  salivary  glands  and  from  there  may  be  passed  into  the  blood 
of  man. 

Plasmodium   Vivax  —  The    Tertian    Parasite.  —  A    sporozoite    or 

merozoite  attacks  a  red  corpuscle  and  gives  rise  to  a  trophozoite  which 

is  at  first   about    one-third   of   the   size   of    the  corpuscle.     It  grows 

rapidly,  acting  deleteriously  on  the  corpuscle,  which  becomes  pale  and 

1  Joum.  of  Exp.  Med,,  xvii.  1913,  p.  374. 


328 


MALARIA   OR  AGUE 


swollen  and  may  show,  after  staining  with  a  Romanowsky  dye,  the 
presence  of  red  granules  called  Schuffner's  dots.  In  about  thirty  hours 
the  parasite  becomes  rounded  to  form  a  schizont,  and  may  measure 
8*5  fx  in  diameter.  From  the  thirtieth  to  the  forty-eighth  hour  the 
schizouts  form  from  fifteen  to  twenty  merozoites,  the  pigment  being 
packed  at  the  periphery  or,  more  commonly,  at  the  centre.  The 
red  corpuscle  is  now  greatly  swollen  and  almost  colourless.  About 
the  forty-eighth  hour  the  remains  of  the  corpuscle  disappear  and  the 
spores  escape.     The  spores  measure  1*5  p. 


Characters  of  the  Different  Malarial  Parasites 


Plasmodium  Vivax. 

Plasmodium  Malaria. 

Laverania  Malarias. 

Schizogon vl  ,0  -, 
completed  in/48  Wa 

Young  tropho-   f1*1*6'  ™T  mo" 
zoite     .         .  1      tile,  long  pseu- 

(     dopodia. 
Schizont.         . -(L^ger  than  red 

I      corpuscle. 

Pigment .         .  "i  Fine,  motile. 

Merozoites         (  15-20  ,  ™ged 
(      regularly. 

Gametocytes    ,{ReseflbIe    schiz" 
J            l      onts. 

Eed  corpuscles  <  Pale  and  swollen 

72  hours. 

Intermediate  in  size, 
movements  slow, 
pseudopodia  short. 

Smaller  than  red 
corpuscle. 

Coarse,  movement 
sluggish,  often 
peripheral,  brown- 
ish. 

6-12  arranged  in  a 
rosette. 

Resemble  schizonts. 

Practically       un- 
affected. 

48  hours  or  less. 
Small,  motile. 

Much  smaller  than  red 
corpuscle. 

Pine,  scanty,  often  non- 
motile. 

8-15  arranged  irregularly. 

Crescent. 

Often  small  and  dark. 

Plasmodium  Malarice — The.  Quartan  Parasite. — The  young  tropho- 
zoite is  smaller  than  that  of  Plasmodium  vivax.  It  shows  little 
protoplasmic  activity,  and  soon  begins  to  produce  pigment  in  the 
form  of  short  rods.  After  twenty-four  hours  the  parasite  is  larger 
and  the  pigment  is  more  abundant.  The  pigment  is  very  dark  in 
colour,  non-motile,  tends  to  accumulate  at  the  periphery,  and  appears 
earlier  and  is  more  obvious  than  in  the  other  forms.  The  infected  red 
corpuscles  may  not  be  much  altered,  or  may  become  rather  smaller 
and  darker  in  colour.  In  about  sixty  hours  the  trophozoite  becomes  a 
schizont,  which  is  a  round  pigmented  body  surrounded  by  the  remains 
of  a  red  corpuscle.  During  the  next  twelve  hours  the  nucleus  breaks 
up  into  six  or  twelve  masses  which,  with  surrounding  cytoplasm,  form 
spores.  The  pigment  is  arranged  in  the  centre,  giving  the  whole  para- 
site a  daisy-like  appearance.  The  merozoites,  measuring  1*75  /*,  are  now 
set  free  and  are  either  killed  off  or  re-enter  blood  corpuscles.     The 


MALAEIA   OR  AGUE  329 

whole  process  of  sporulation  takes  place  in  the  peripheral  blood   and 
occupies  seventy-two  hours. 

Laverania  Malaria? — The  JEstivo- Autumnal  Parasite. — The  young 
trophozoite  is  exceedingly  small.  It  soon  assumes  a  delicate  ring  shape, 
and  measures  about  1  /*  in  diameter.  It  grows  into  an  oval  form, 
which  becomes  pigmented.  The  reel  corpuscles  may  degenerate,  some  of 
them  acquiring  a  curious  brassy  appearance,  and  others,  in  specimens 
stained  by  Leishman's  method,  showing  large  irregular  red  streaks  or 
dots,  known  as  Maurer's  dots.  The  full-grown  schizont  measures  4*5  /*. 
It  is  very  rarely  seen  in  the  peripheral  blood.  Segmentation  takes 
place  in  the  spleen  and  other  organs.  The  merozoites  number  eight 
to  fifteen  and  measure  07  ^.  Schizogony  is  completed  in  from  thirty- 
six  to  forty-eight  hours. 

The  gametocytes  differ  in  shape  from  the  schizonts.  They  are 
characterised  by  being  crescent-shaped,  and  usually  show  the  remains 
of  a  red  cell  stretched  round  them. 

The  macrogametocyte  is  long  and  thin  and  has  comparatively  dark- 
coloured  cytoplasm.  The  chromatin  is  compact  and  is  surrounded  by 
pigment.  The  microgametocy  te  is  shorter  and  broader.  The  protoplasm 
is  more  hyaline,  the  chromatin  more  diffuse,  and  the  pigment  more 
scattered.  Flagellated  forms  are  sometimes  seen  in  specimens  of  blood, 
but  such  forms  are  properly  part  of  the  life  cycle  in  the  mosquito. 
Possibly  their  occurrence  in  films  is  determined  by  exposure  to  air 
or  artificial  conditions.  They  may  be  brought  out  by  adding  water  to 
the  blood. 

It  is  to  be  noted  that  it  is  common  in  any  type  and  in  any  case 
in  which  the  parasites  are  numerous  to  find  two  plasmodia  in  a 
single  corpuscle. 

B.  In  the  Mosquito — Sporogony. — If  the  female  mosquito  in  her  search 
for  nourishment  for  her  eggs  sucks  blood  from  a  person  whose  circulating 
fluid  contains  macro-  and  microgametocy tes,  a  sexual  cycle  of  the  para- 
site's life-history  begins.  The  macrogametocyte  undergoes  reduction  by 
division  of  its  nucleus  and  formation  of  polar  bodies.  It  is  now  known 
as  a  macrogamete  (Fig.  27,  fl).  The  microgametocyte  undergoes  a  some- 
what similar  change.  It  throws  out  four  to  six  thread-like  protoplasmic 
projections.  Chromatin  masses  separate  from  the  nucleus  and  pass  into 
these  threads  in  the  form  of  dots  and  bars.  These  flagella-like  bodies 
lash  about  vigorously,  then  break  off,  and  are  known  as  microgametes 
(Fig.  27,  m1).  A  microgamete  now  conjugates  with  a  macrogomete  and 
the  male  and  female  pronuclei  fuse  and    form  a  zygote — the  ookinete. 


330  MALAKIA  OR  AGUE 

The  zygote  elongates  and  its  anterior  extremity  becomes  pointed.  It 
now  pierces  the  epithelium  of  the  mosquito's  stomach  and  under  the 
epithelium  forms  a  thin-walled  cyst — the  oocyst.  This  cyst  grows 
rapidly,  the  nucleus  divides  to  form  a  large  number  of  daughter  nuclei 
which,  with  their  surrounding  protoplasm,  form  the  sporoolasts.  The 
sporoblast  nuclei  further  divide  and  pass  into  projections  of  the 
cytoplasm.  Each  of  these  projections  with  its  chromatin  particle  is  a 
sporozite.  Eventually  the  oocyst  bursts  into  the  ccelom  of  the  mosquito 
and  the  sporozoites  enter  the  blood-stream  and  are  carried  all  over  the 
insect's  body.  Finally  they  find  their  way  to  the  salivary  glands,  where 
they  are  ready  to  infect  a  new  host.  Possibly  they  may  be  carried  by 
the  eggs  to  a  new  generation  of  mosquitoes. 

Conditions  Favouring  Infection. — The  most  important  condition 
favouring  infection  is  residence  in  a  malarial  district.  By  that  we 
understand  a  district  where  there  are  infected  persons  carrying 
gametocytes  in  their  blood,  where  there  are  mosquitoes  capable  of  carrying 
the  parasite,  and  where  the  climatic  conditions  are  favourable  to  the 
growth  of  the  parasite  in  the  mosquito.  A  temperate  or  warm  climate 
is  thus  essential  as  well  as  moist  or  marshy  areas  for  the  development 
of  the  mosquito.  A  wet  season  may  therefore  be  an  important  pre- 
disposing cause. 

Foetal  malaria  may  occur,  but  is  exceedingly  rare.  Children,  being 
more  exposed  to  mosquito  bites,  are  specially  liable  to  infection. 
Occupation  may  play  a  part  in  subjecting  persons  to  increased  risk  of 
infection. 

Conditions  Favouring  Development  of  the  Parasite  after  Infection. — 
Attacks  of  malaria  appear  to  confer  a  certain  degree  of  immunity. 
Natives  of  a  malarial  district  are  less  subject  to  the  disease  than 
immigrants.  Lowered  conditions  of  health  from  any  cause — starvation, 
chills,  or  chronic  ailments — appear  to  diminish  the  resistance  of  the  body 
to  the  development  of  the  parasite. 

Pathology. — The  parasites  by  their  growth  cause  destruction  of  the 
red  blood  corpuscles  and  at  the  same  time  liberate  toxins  which  are 
capable  of  causing  fever  and  a  certain  degree  of  haemolysis.  The  quartan 
parasites,  until  they  sporulate,  do  practically  no  damage  to  the  red 
corpuscles,  and  thus  sporulating  forms  are  readily  found  in  the  peripheral 
blood.  The  tertian  and  sestivo-autumnal  forms,  on  the  other  hand, 
markedly  affect  the  red  corpuscles  they  inhabit,  and  therefore  these  are 
arrested  by  the   endothelium  of  the  internal   organs,  particularly  the 


MALAEIA   OE  AGUE  331 

spleen,  bone-marrow,  and  liver.  Sporulating  tertian  forms  are  thus  rare 
in  the  peripheral  blood,  and  sporulating  a?stivo-autumnal  forms  are  very 
rare.  The  latter  parasite  may  bring  about  serious  damage  by  causing 
red  corpuscles  to  agglutinate  and  form  thrombi  in  the  vessels  of  the 
brain  or  internal  organs.  During  sporulation  the  parasites  liberate 
pigment,  which  becomes  deposited,  sometimes  in  large  amount,  in  the 
organs  where  sporulation  occurs.  It  is  also  taken  up  by  the  leucocytes, 
and  may  be  carried  throughout  the  body.  During  sporulation  toxins 
are  liberated.  It  follows  that  the  paroxysms  of  fever  are  determined 
by  this  phase  of  the  life-history  of  the  parasite.  The  red  corpuscles 
destroyed  by  the  parasites,  mechanically  and  chemically,  set  free  a 
considerable  amount  of  pigment  which  is  found  as  hemosiderin,  most 
abundantly  in  the  liver,  but  also  in  the  spleen,  kidneys,  and  bone-marrow. 
Death  from  either  quartan  or  simple  tertian  malaria  is  very  rare.  The 
pathological  findings  include  the  presence  of  parasites,  malarial  pigment, 
and  blood-pigment  in  the  organs,  enlargement  of  the  spleen,  and  the 
conditions  usually  associated  with  a  toxic  febrile  affection. 

In  sestivo-autumnal  fever  the  lesions  found  may  be  more  severe. 
The  skin  may  show  a  yellowish  colour.  The  intestines  may  be  pigmented 
and  inflamed,  the  liver  enlarged,  soft,  and  dark  in  colour.  Its  capillaries 
are  dilated,  and  their  endothelium  is  swollen  and  pigmented.  The  liver 
cells  are  compressed  and  may  be  necrosed.  They  contain  iron-pigment. 
The  spleen  is  enlarged,  the  capsule  is  tense,  the  pulp  is  soft,  the  red  cells 
contain  schizonts  and  crescents.  Pigment  is  present  in  large  lympho- 
cytes and  endothelium.  The  kidneys  show  pigmentation  of  the  capillary 
walls,  and  parasites  are  common  in  the  intertubular  capillaries.  Varying 
degrees  of  nephritis  may  be  found.  The  bone -marrow  may  show  an 
extension  of  hemopoietic  tissue  from  the  extremities  towards  the 
centre  of  the  shaft  of  the  long  bones.  It  is  always  pigmented  and  rich 
in  parasites. 

In  chronic  malaria  and  malarial  cachexia  there  are  cirrhotic  changes 

o 

in  the  organs,  and  the  spleen  and  liver  may  be  greatly  enlarged.  The 
bone-marrow  may  become  sclerotic  or  gelatinous.  Parenchymatous 
nephritis  and  waxy  disease  sometimes  supervene. 

Symptoms. — The  symptoms  caused  by  the  three  parasites  have  a 
general  resemblance,  but  the  course  and  severity  of  the  different  fevers 
vary  considerably. 


332  MALAEIA   OR  AGUE 

1.    Symptoms  due  to  Plasmodium  Vivax 

(a)  Simple  Tertian  Fever. — Simple  tertian  fever  is  characterised  by- 
paroxysms  of  fever  occurring  every  forty-eight  hours  and  separated  by 
an  interval  corresponding  to  the  length  of  time  taken  by  the  parasite  to 
develop  from  the  merozoite  to  the  fully-developed  schizont. 

Prodromata. — Prodromal  symptoms  may  be  absent  but  certain 
symptoms  may  arise  from  sporulation  of  parasites  not  numerous  enough 
to  cause  fever.  These  symptoms  include  great  lassitude  and  weakness, 
headache,  and  pains  in  the  back,  extremities,  and  joints.  Treatment  at 
this  stage  may  abort  an  attack.  In  any  case  symptoms  will  have  dis- 
appeared on  the  following  day.  If  untreated  the  patient  will  probably 
show  febrile  symptoms  on  the  next  day.  The  attack  may  begin  at  any 
time,  but  frequently  starts  in  the  early  morning.  Symptoms  are  usually 
ushered  in  by  an  attack  of  nausea  or  vomiting,  and  there  may  be  a 
slight  rise  of  temperature.  The  cycle  of  events  is  then  a  cold  stage 
succeeded  by  a  warm  stage  and  a  sweating  stage.  In  children  the 
paroxysm  may  be  ushered  in  by  convulsions,  and  the  cold  stage  and 
sweating  may  be  absent. 

The  cold  stage  is  associated  with  an  actual  feeling  of  chilliness  and 
marked  rigors.  The  shivering  may  shake  the  patient's  bed.  His  teeth 
chatter,  his  lips  look  blue,  and  goose-skin  may  be  noticed.  During 
this  stage  the  temperature  is  steadily  rising,  and  in  spite  of  the  out- 
ward manifestations  of  cold  the  rectal  temperature  may  reach  104°  or 
105°  F.     In  from  ten  to  twenty  minutes  this  phase  has  passed. 

The  warm  stage  begins  with  fleeting  sensations  of  warmth,  which, 
at  first,  are  rather  welcomed  by  the  patient.  They  increase  in  intensity 
and  duration,  and  soon  the  patient  is  uncomfortably  hot.  The  tempera- 
ture may  continue  to  rise.  The  mouth  is  dry,  and  herpes  may  appear 
on  the  lips.  Vomiting,  and  more  rarely  diarrhoea,  may  occur.  The 
spleen  is  enlarged  and  tender  and  a  soft  murmur  may  be  heard  over  it 
on  auscultation.  The  pulse  is  rapid,  its  volume  is  large,  and  the  dicrotic 
wave  may  be  palpable.  A  temporary  soft  systolic  cardiac  murmur  is 
sometimes  audible.  A  slight  cough  may  be  noticed,  and  rhonchi  and 
coarse  crepitations  may  be  detected.  The  skin  is  hot  and  dry.  Skin 
eruptions  sometimes  occur ;  they  are  usually  urticarial  or  erythematous. 
The  skin  and  conjunctivas  may  show  a  yellowish  tinge.  The  headache 
and  pains  in  the  limbs  generally  increase.  This  stage  may  last  as  long 
as  five  hours. 

Sweating  Stage. — A  gentle  perspiration  is  rapidly  followed  by  profuse 


MALAEIA   OK   AGUE  333 

sweating  all  over  the  body.  The  sweat  has  a  characteristic  odour.  The 
pulse,  respirations,  and  temperature  fall  to  normal  in  about  four  hours. 
The  patient  generally  falls  asleep  and  awakens  feeling  comparatively 
well  but  somewhat  weak. 

In  the  apyrexial  interval,  which  lasts  about  thirty-six  hours,  the 
patient's  temperature  may  be  subnormal.  The  blood  shows  developing 
parasites  and  various  changes  in  the  cellular  elements,  to  be  described 
later.  The  feeces  show  an  increase  of  iron  and  bile  products.  During 
the  attack  the  urine  is  at  first  increased  in  quantity.  It  is  dark  coloured 
and  very  acid  in  reaction.  No  th  with  standing  the  increased  quantity,  the 
specific  gravity  is  increased,  due  to  more  rapid  metabolism  and  a  conse- 
quently greater  output  of  solids.  Nitrogen,  chlorides,  and  sulphates  are 
increased.  Phosphates  are  diminished  during  the  attacks.  Urobilin 
may  be  increased.  Albuminuria  sometimes  occurs.  The  diazo-reaction 
is  occasionally  obtained.  During  the  intermission  the  quantity  of  urine 
falls,  but  there  is  still  an  increased  output  of  solids.  The  output  of 
phosphates  is  now  increased.  Sulphates  remain  abundant.  Chlorides 
are  diminished.     Iron  is  markedly  increased. 

During  convalescence  there  may  be  very  marked  polyuria. 

Course. — Tertian  malaria  tends  towards  a  spontaneous  cure  after 
several  paroxysms.  The  incidence  of  the  attacks  varies  both  as  regards 
severity  and  time.  Anticipating  attacks  sometimes  occur.  In  these 
there  is  a  shortening  of  the  apyrexial  interval.  Lengthening  of  the 
interval  is  referred  to  as  retardation  of  the  attacks,  and  is  generally 
due  to  the  exhibition  of  quinine,  but  may  be  due  to  weakening  of  the 
parasite  from  some  other  cause. 

(b)  Doiible  Tertian  Fever. — This  condition  is  due  to  infection  with 
two  broods  of  parasites  which  mature  on  different  clays.  As  sporulation 
of  one  or  other  occurs  every  day,  the  result  is  a  quotidian  fever.  As  a 
rule  the  attacks  begin  at  the  same  time  each  day,  but  the  attack  due  to 
one  brood  may  be  later  than  the  other.  The  attacks  may  not  be  of  the 
same  severity,  but  if  untreated  the  weaker  tends  in  time  to  equal  the 
more  severe.  In  a  double  infection  the  duration  of  the  individual 
paroxysm  is  usually  shorter.  Double  tertian  fever  may  also  arise 
through  anticipation  of  a  simple  tertian  infection. 

(c)  Irregular  Tertian  Fever. — Different  broods  of  parasites  may 
sporulate  at  different  times  on  the  same  day,  and  an  almost  continuous 
fever  may  result. 


334  MALAPJA   OE  AGUE 

2.  Symptoms  due  to  Plasmodium  Malarle 

(a)  Simple  Quartan  Fever. — A  paroxysm  occurs  every  seventy-two 
hours. 

Prodromata. — Prodromal  symptoms  are  the  rule,  and  are  similar  to 
those  found  in  tertian  fever. 

The  cold  stage  lasts  from  fifteen  to  thirty  minutes,  and  if  the  blood 
be  examined  sporulating  forms  and  young  forms  of  the  parasite  may 
be  found. 

The  hot  stage  lasts  from  three  to  six  hours. 

The  sweating  stage  lasts  a  few  hours. 

Course. — Quartan  fever  has  a  special  tendency  to  relapse.  The 
febrile  paroxysm  and  resulting  anaemia  may  be  severe,  but  the  parasite 
does  not  multiply  in  sufficient  numbers  to  cause  pernicious  symptoms, 
and  does  not  accumulate  in  internal  organs  in  sufficient  numbers  to 
cause  serious  local  disease. 

(b)  Double  Quartan  Fever. — This  condition  is  caused  by  two  broods 
of  parasites  inoculated  on  different  days.  The  attacks  of  fever  occur  on 
two  successive  days,  followed  by  a  remission  of  twenty-four  hours.  The 
attacks  caused  by  the  different  broods  are  not  always  of  the  same 
intensity. 

(c)  Triple  Quartan  Fever. — This  is  caused  by  three  broods  of  quartan 
parasites  coming  to  maturity  on  three  successive  days.  The  result  is  a 
quotidian  fever. 

(d)  Irregular  Quartan  Fever. — A  multiple  infection  may  result  in  an 
almost  continuous  fever. 

A  multiplication  of  parasites  introduced  originally  in  small  numbers 
may  convert  a  simple  into  a  double  or  a  double  into  a  triple  quartan 
fever.  On  the  other  hand,  weakening  of  a  strain  of  parasites  in  a  triple 
infection  may  reduce  it  to  a  double  or  even  a  simple  quartan  type. 

3.  Symptoms  due  to  Laverania  Malarle 

The  fevers  caused  by  this  parasite  are  known  as  sestivo-autumnal 
or  subtertian  fevers.  The  latter  name  is  derived  from  the  fact  that 
the  fever  is  essentially  tertian  in  type  although  the  attacks  may  be 
greatly  prolonged. 

(a)  Simple  Subtertian  Fever. — The  incubation  period  is  thought  to 
be  nine  or  ten  days.  Prodromal  symptoms  like  those  of  simple  tertian 
fever  are  common.      The  cold  stage  may  be  severe,  but  is  sometimes 


MALAEIA   OE   AGUE  335 

absent.  The  hot  stage  is  associated  with  severe  headache  and  pains  in 
the  back  and  limbs.  Gastro-intestinal  disturbances  are  common,  and 
there  may  be  jaundice.  The  temperature  rises  rapidly  to  104°  or 
105°  F.,  and  remains  high  with  slight  oscillations.  There  is  often  a 
considerable  fall  just  before  the  crisis  (pseudo-crisis).  The  temperature 
then  reaches  its  highest  point  (precritical)  and  the  sweating  stage  and 
a  rapid  fall  (crisis)  supervene.  The  temperature  generally  remains 
subnormal  till  the  next  attack.  The  duration  of  the  paroxysm  is  often 
about  twenty-four  hours.  The  duration  of  the  attack  in  hours  deducted 
from  forty-eight  will  give  the  length  of  the  interval. 

(b)  Double  Subtertian  Fever. — This  is  due  to  a  double  infection, 
leading  to  a  quotidian  fever.  The  attacks  are  usually  comparatively 
short  (six  to  twelve  hours). 

(c)  Irregular  Subtertian  Fevers. — A  multiple  infection  may  lead  to  a 
continuous  fever,  with  exacerbations  when  a  numerous  brood  sporulates. 
Eemittent  fevers  may  arise  from  prolongation  of  ordinary  paroxysms, 
so  that  one  attack  is  not  over  before  another  occurs.  A  remittent  type 
of  fever  may  occur  as  the  result  of  anticipating  attacks.  These  fevers 
are  often  associated  with  sleeplessness  and  delirium.  In  some  cases 
the  condition  may  resemble  typhoid  and  in  others  there  may  be 
haemorrhages.     A  scarlatiniform  rash  may  occur. 

Bilious  remittent  fever  is  a  type  associated  with  jaundice,  bilious 
vomiting,  and  sometimes  bilious  diarrhoea.  The  stomach  and  liver  may 
be  very  tender.  Symptoms  may  subside,  but  vomiting,  hsematemesis, 
hiccough,  sometimes  epistaxis  and  other  haemorrhages  occur,  and  the 
temperature  rises  greatly  and  coma  and  death  supervene. 

(d)  Pernicious  Malaria.— Specially  severe  symptoms  may  arise  either 
from  a  very  severe  infection,  causing  a  marked  general  toxaemia,  or  from 
a  special  accumulation  of  the  parasites  in  some  particular  organ,  deter- 
mining severe  local  symptoms.  In  either  case  a  high  mortality  is  the 
result.     Several  types  have  been  described. 

Algid  Pernicious  Malaria. — This  is  a  very  serious  condition  in 
which  the  patient  appears  in  a  condition  of  collapse.  The  features  are 
sharp,  the  lips  blue,  the  pulse  rapid  and  of  very  low  pressure,  the  skin 
cold  and  clammy.  Coma  supervenes,  and  death  generally  occurs  in  a 
few  hours. 

Diaphoretic  Pernicious  Malaria. — In  this  type  the  sweating  stage  may 
be  so  marked  that  the  bed  and  floor  may  be  saturated  with  perspiration. 
The  patient  becomes  exhausted,  and  death  from  collapse  is  common. 

Hwmorrliagic   Pernicious   Malaria. — This    form   is   associated   with 


336  MALAEIA   OE  AGUE 

haemorrhages,  it  may  be  from  almost  all  the  mucous  membranes, 
during  the  paroxysms.  A  very  severe  anaemia  is  rapidly  produced. 
Delirium,  convulsions,  coma,  and  death  generally  result. 

Cerebrospinal  Type  of  Pernicious  Malaria. — Almost  any  nervous 
lesion  may  result  from  malaria.  The  parasites  may  accumulate  in  the 
capillaries  of  the  brain  and  generate  toxins,  while  the  combined  effect 
of  swollen  endothelium,  agglutinated  red  corpuscles,  parasites,  and 
pigment  may  lead  to  blocking  of  capillaries  or  actual  thrombosis. 
Symptoms  may  be  of  a  general  cerebral  type  or  may  indicate  a  more 
localised  lesion.  Coma  is  a  common  occurrence.  It  is  sometimes 
recovered  from,  but  may  return,  the  second  attack  usually  being  fatal. 
Delirium  may  be  an  early  and  prominent  symptom  and  is  seldom 
followed  by  recovery.  Symptoms  resembling  those  of  tetanus  may  occur, 
and  convulsions  are  not  uncommon.  More  localised  lesions  may  lead  to 
hemiplegia,  blindness,  or  aphasia.  Symptoms  may  indicate  an  intensity 
of  the  condition  in  the  medulla,  cerebellum,  or  cord.  Malarial  meningitis 
may  occur. 

Gastro-Intestinal  Type  of  Pernicious  Malaria. — Symptoms  resembling 
those  of  cholera  or  dysentery  are  commonly  met  with.  A  fair  propor- 
tion of  such  cases  recover.  Acute  haemorrhagic  pancreatitis  has  been 
found  post-mortem  in  some  cases. 

Chronic  Malaeia 

This  condition  may  result  from  infection  with  any  of  the  parasites, 
but  is  usually  due  to  Laverania  malariae. 

The  symptoms  include  repeated  attacks  of  slight  fever,  pigmentation 
of  the  skin  and  mucous  membranes,  and  slight  yellow  colouration  of  the 
skin  in  many  cases. 

The  urine  shows  an  increased  output  of  urea  and  urobilin.  The 
liver  and  spleen  are  enlarged.  There  is  great  lassitude  and  often  severe 
anaemia.  During  febrile  attacks  parasites  may  be  found  in  the  blood. 
A  continuance  of  this  condition  leads  to  malarial  cachexia,  in  which 
there  is  emaciation  and  enormous  enlargement  of  the  spleen,  which  is 
firm  and  not  tender.  Traumatic  and  even  spontaneous  rupture  of  the 
spleen  may  occur.  Parasites  are  not  readily  found  in  the  blood  unless 
a  febrile  attack  should  occur. 

A  person  who  has  once  had  malaria  is  liable  to  have  occasional 
attacks  months  or  years  after  the  date  of  infection. 

In  latent  malaria  parasites,  usually  aestivo-autumnal  forms,  may  be 


MALAEIA   OE   AGUE  337 

found  in  the  blood  although  symptoms  are  absent.     The  parasites  are 
usually  crescents,  which,  according  to  Eoss  and  Thomson,  persist  by 
constant  regeneration  but  do  not  live  long  individually. 
Sexual  forms  do  not  cause  fever. 

The  Blood  in  Malaria. — The  parasites  inhabit  the  red  corpuscles 
and  may  be  seen  in  fresh  specimens.  The  movements  of  the  parasites 
and  of  their  pigment  readily  attract  attention,  particularly  in  tertian 
fever,  the  Plasmodium  vivax  being  specially  active.  The  finer  structure 
of  the  parasite  can  only  be  determined  in  stained  specimens.  Thin 
evenly-spread  films  give  the  best  results,  but  if  a  mere  rapid  diagnosis 
is  required,  then  the  method  introduced  by  Eoss  may  be  employed. 
Many  variations  in  the  technique  have  been  suggested. 

1.  A  large  drop  of  blood  is  spread  out  on  a  slide  and  allowed 
to  dry  in  air  or  slightly  heated.  The  film  is  then  covered  with  an 
aqueous  solution  of  eosine  and  stained  for  fifteen  minutes.  It  is 
next  washed  gently  and  the  red  corpuscles  lose  their  haemoglobin. 
The  film  is  then  stained  for  a  few  seconds  with  alkaline  methylene 
blue,  washed,  dried,  and  mounted.  Or  the  alkaline  methylene  blue 
may  be  used  in  very  dilute  solution,  and  the  stain  correspondingly 
prolonged. 

2.  Another  method  is  fixation  in  absolute  alcohol,  dehaernoglobinisa- 
tion  with  1  per  cent,  acetic  acid,  and  subsequent  staining ;  or  fixation 
may  be  carried  out  with  acid  alcohol  (5  per  cent,  acetic  acid  in  absolute 
alcohol). 

3.  Films  may  have  their  haemoglobin  washed  out  with  water  and 
then  staining  is  effected  with  Leishman's  dye. 

4.  We  find  that  we  get  excellent  results  with  the  least  possible 
trouble  by  immersing  the  thick  film  as  soon  as  it  has  dried  in  a  very 
dilute  solution  of  Leishman's  stain  in  tap  water.  Twenty  to  thirty 
drops  of  the  dye  in  an  ounce  of  water  is  sufficiently  strong.  The  film 
may  be  left  in  this  for  an  hour  or  more.  The  length  of  time  taken 
in  staining  depends  a  good  deal  on  the  thickness  of  the  film,  and  it  is 
well  for  beginners  to  control  it  by  occasional  microscopic  examination 
under  a  medium  power.  When  staining  is  complete  the  whole  film 
has  a  transparent  blue  colour.  It  is  then  rinsed  gently  with  water, 
allowed  to  dry,  and  mounted  in  balsam. 

The  advantage  of  these  methods  is  that  a  much  larger  quantity 

of  blood  can  be  examined  quickly  than  by  the  ordinary  film  method. 

The  staining  of  the  plasmodia  is  the  same,  and  as  nothing  is  left  in  the 

22 


338  MALARIA    OR  AGUE 

film  except  the  leucocytes,  the  plasmodia,  and  the  fibrin  threads  which 
hold  them  in  position,  the  search  for  parasites  is  much  easier,  especially 
in  cases  where  they  are  few  in  number. 

Any  basic  dye  will  demonstrate  the  parasites  in  ordinary  films, 
but  the  best  results  are  obtained  by  the  use  of  a  Romanowsky  dye. 
We  prefer  Leishman's  method.  The  nuclear  chromatin  stains  a  bright 
red  with  the  azur  contained  in  the  mixture.  The  characters  of  the 
parasites  have  been  described  in  discussing  their  life-history  and  are 
illustrated  in  Plate  XV. 

Thomson l  has  devised  a  special  pipette  for  the  enumeration  of  the 
actual  number  of  parasites  in  a  unit  of  blood,  and  it  may,  of  course, 
be  used  to  count  other  parasites,  such  as  trypanosomes,  and  also  leuco- 
cytes. From  our  experience  of  it  we  are  conservative  enough  to  prefer 
the  older  method  of  leucocyte  counting,  but  there  seems  no  doubt  that 
in  expert  hands  it  is  capable  of  giving  accurate  results,  and  it  is 
■certainly  the  best  means  of  enumerating  parasites.  The  pipette,  which 
is  made  by  C.  Baker,  244  High  Holborn,  London,  is  a  capillary  tube 
made  of  thick  glass,  graduated  in  -J  of  a  c.mm.  The  blood  is  drawn 
directly  into  the  tube,  -J  c.mm.  is  then  blown  out  on  a  clear  glass  slide, 
kept  moist  by  breathing  on  it,  and  spread  out  with  a  needle  into  a 
square  4  mm.  x  4  mm.  This  film  is  allowed  to  dry  and  then  stained 
as  usual.  It  must  be  examined  with  a  mechanical  stage,  an  immersion 
lens,  and  a  square  diaphragm  in  the  eye-piece.  The  counting  is  done 
by  finding  the  number  of  fields  from  top  to  bottom  of  the  square,  and 
counting  bands  across  the  whole  film  at,  say,  the  5th,  10th,  and  15th 
fields  from  the  top.  If  the  number  of  fields  from  top  to  bottom  be  30, 
and  the  average  number  of  leucocytes  in  each  band  be  40,  then  the 
total  number  in  the  square  film  is  30x40  =  1200.  The  square  film 
represents  -J-  c.mm.,  so  the  number  per  c.mm.  is  8x1200  =  9600.  It  is 
obvious  that  the  accuracy  of  the  result  will  depend  entirely  on  the  even 
spreading  of  the  film,  and  that  uneven  spreading  can  only  be  overcome 
by  counting  the  whole  square  film.  One  great  advantage  of  the  method 
is  that  the  specimens  can  be  stored  for  reference. 

The  pipette  must  be  cleaned  at  once  with  water,  alcohol,  and  ether 
successively.  Blocked  pipettes  may  be  cleared  by  immersing  them  in 
a  test-tube  containing  nitric  acid,  and  placing  the  test-tube  in  a  beaker 
of  water  which  is  alternately  boiled  and  cooled. 

The  blood  in  malaria  may  be  profoundly  altered. 

1  Ann.  of  Trop.  Med.   and  Parasit.,  December   1911.      Med.  Press,  24th   April 
1912. 


MALAKIA   OR   AGUE  339 

Bed  Corpuscles. — As  every  sporulation  causes  destruction  of  the 
infected  red  cells,  anaemia  is  always  a  feature  of  malaria.  This  is 
usually  mild  in  tertian  and  quartan,  but  may  be  very  severe  in  aestivo- 
autumnal  fever.  In  tertian  fever  the  infected  red  cells  are  enlarged 
and  partially  decolourised. 

Specimens  prepared  with  Leishman's  stain  may  show  fine  red  points 
(Schuffner's  dots)  in  some  of  the  infected  red  cells.  These  are  probably 
the  result  of  degeneration.  In  quartan  malaria  the  infected  reel  cells 
are  rather  smaller  than  normal,  and  exhibit  a  slightly  darker  colour. 
In  sestivo-autumnal  fever  the  infected  corpuscles  may  become  de- 
colorised, particularly  those  containing  crescents.  Some  of  the 
corpuscles  show  Schuffner's  dots  and  others  show  larger  and  more 
irregular  areas,  which  stain  red  with  Leishman's  dye.  These  are  known 
as  Maurer's  dots.  Again,  some  of  the  red  cells  become  shrunken,  and 
in  fresh  specimens  show  a  brassy  colour. 

In  attacks  of  ordinary  severity  the  anaemia  induced  by  one  paroxysm 
has  to  a  considerable  extent  been  recovered  from  before  another  takes 
place,  but  even  in  quartan  fever,  if  long  continued,  secondary  anaemia 
may  result.  This  may  assume  the  picture  of  an  ordinary  secondary 
anaemia  with  the  characteristic  alteration  of  the  leucocytes,  or  there 
may  be  very  marked  blood  changes,  not  merely  due  to  blood  destruc- 
tion by  the  parasites  and  their  toxins,  but  also  to  damage  to  the 
bone-marrow. 

The  milder  changes  include  poikilocytosis,  anisocytosis,  a  low  colour 
index,  and  the  presence  of  a  few  normoblasts.  In  more  severe  cases 
there  are  in  addition  polychromasia,  punctate  basophilia,  and  megalo- 
blasts  and  megalocytes,  with  a  colour  index  tending  to  be  high. 
Prognosis  in  such  cases  is  very  grave.  In  another  type  of  anaemia 
there  is  little  indication  of  bone-marrow  reaction.  The  red  cells  are 
small  and  misshapen,  greatly  reduced  in  number,  polychromasia  is 
absent  or  slight,  and  nucleated  red  cells  are  scanty  or  absent.  Prog- 
nosis is  also  grave,  but  the  course  is  more  prolonged  than  in  the 
megaloblastic  type  of  anaemia. 

Leucocytes. — During  the  paroxysms  there  is  usually  at  the  very 
beginning,  and  lasting  for  about  half  an  hour,  a  more  or  less  marked 
leucocytosis,  polymorphonuclear  cells  being  specially  increased.  This 
is  succeeded  by  leucopenia,  affecting  the  total  numbers  of  both  poly- 
morphs and  lymphocytes,  which  is  most  marked  at  the  end  of  the 
paroxysms  and  continues  in  the  apyretic  intervals.  Differential  counts 
during  the  intervals  show  an  increase  of  large  lymphocytes,  particu- 


340  MALAEIA   OK  AGUE 

larly  of  the  large  mononuclear  or  large  hyaline  type.  Polymorphs 
range  from  40  to  65,  large  lymphocytes  from  15  to  40,  small  lympho- 
cytes from  15  to  20  per  cent.  Eosinophils  are  usually  less  than  1  per 
cent.  In  some  cases  the  lymphocyte  percentage  may  be  even  higher — 
up  to  90  per  cent. 

Arneth's  classification  shows  a  drift  to  the  left  and  a  few  myelocytes 
may  be  seen,  especially  in  the  severe  cases  with  megaloblastic  ansemia. 
Many  of  the  large  lymphocytes,  a  few  polymorphs,  and  an  occasional 
eosinophil  may  be  seen  containing  pigment.  Large  lymphocytes  may 
show  phagocytosis  towards  the  parasites  and  red  cells  containing  them. 
It  is  quite  evident  that  lymphocytes,  especially  the  large  forms,  are  the 
active  agents  of  defence  in  malaria.  They  vary  in  percentage  and  total 
number  inversely  with  the  temperature,  being  low  when  it  is  high,  and 
rising  at  once  when  it  falls.1 

In  the  chronic  forms  there  is  leucopenia  with  a  high  percentage 
of  lymphocytes,  especially  the  larger  forms.  In  the  severe  sestivo- 
autumnal  forms  there  may  be  a  considerable  increase  in  the  total 
number  of  white  cells — up  to  30,000  or  more.  This  is  usually  a  real 
lymphocytosis. 

Thomson  (I.e.)  asserts  that  in  quiescent  or  latent  malaria,  and  in 
cases  apparently  cured  by  quinine,  the  lymphocyte  fluctuation  is 
replaced  after  a  certain  time — a  few  days  up  to  a  week  in  mild  cases,. 
ten  days  or  longer  in  severe  cases  or  debilitated  persons — by  a  poly- 
morph fluctuation.  This  takes  the  form  of  a  leucocytosis,  rising  even 
to  125,000,  and  often  as  high  as  40,000,  which  lasts  only  a  few  hours 
or  even  less,  and  is  markedly  periodic  in  occurrence,  being  quotidian,, 
tertian,  irregular,  etc.,  according  to  the  type  of  the  original  fever,  and 
coming  on  at  the  same  time  of  day  as  the  original  attack.  The  cause 
of  this  phenomenon  is  uncertain,  but  must  apparently  be  the  persistence 
of  some  periodic  virus,  it  may  be  the  sporulation  of  a  very  small  number 
of  parasites.  If  this  is  so,  it  is  certainly  remarkable  that  the  sporula- 
tion of  a  large  number  of  parasites  should  cause  a  leucopenia,  and  of  a 
small  number  a  leucocytosis. 

Times  at  vjhich  to  Examine  the  Blood  for  Parasites. — Parasites  can 
be  found  in  the  blood  during  the  chill,  but  from  eight  to  ten  hours 
after  the  commencement  of  the  tertian  rigor  they  are  usually  most 
numerous,  and  this  time  has  the  further  advantage  that  the  char- 
acteristic leucopenia  is  usually  present.  In  simple  tertian  fever  most 
of  the  plasmodia  are  now  seen  as  rings.  The  amoeboid  forms  appear 
1  Thomson,  Ann.  of  Trop.  Med.  and  Parasit.,  April  1911. 


Plate  XVI. — Blood  Film  from  Case  of  Tertian  Malaria,  taken  Twenty- 
six  Hours  after  the  Beginning  of  a  Paroxysm  (Leish man's  Stain). 

There  are  no  young  forms. 

Trophozoites  and  schizonts  are  present ;  large  lymphocytes  show  pigment.     In  the  lower  one  are 
also  azur  granules. 


A.  G.,  feoit. 


MALAEIA  OR  AGUE  341 

from  this  time  onwards  to  the  end  of  the  first  twenty-four  hours. 
For  the  next  twelve  hours  the  full-grown  parasites  are  seen,  in  the 
form  of  large  spherical  bodies  containing  much  pigment,  while  the 
form  preceding  segmentation  appears  generally  about  eight  hours 
before  the  next  rigor  is  due.  Eosettes  appear  about  three  or  four 
hours  before  the  rigor,  are  most  numerous  just  before  it  occurs,  and 
quickly  disappear  after  it. 

In  cases  where  there  is  any  doubt  about  the  diagnosis  care  should  be 
taken  not  to  give  quinine  until  after  films  have  been  made,  unless  the 
symptoms  are  so  urgent  as  to  make  immediate  treatment  imperative. 
Even  in  cases  treated  with  quinine  parasites  may  be  found  up  to  eighteen 
hours  after  the  rigor,  but  they  are  usually  very  scanty. 

The  appearances  of  the  quartan  parasite  correspond  roughly  to  those 
of  the  tertian,  with  the  necessary  lengthening  of  the  time  involved. 
This  affects  rather  the  period  of  growth  in  the  middle  of  the  cycle  than 
the  incidence  at  beginning  and  end. 

In  sestivo-autumnal  fever  the  small  rings  may  be  found  at  about  the 
same  time  as  in  tertian.  The  characteristic  signet-ring  form  appears 
about  twenty-four  hours  after  the  rigor;  thereafter  the  appearance  of 
parasites  varies  greatly  in  different  cases.  In  some  the  amoeboid  forms 
are  very  scanty  or  apparently  absent,  and  in  cases  treated  by  quinine 
they  often  disappear  about  the  third  day.  In  others  they  are  numerous, 
and  may  persist  for  nearly  a  week.  Segmentation  occurs  in  the  internal 
organs,  not  in  the  blood.  Crescents  are  generally  to  be  found  after  the 
fourth  day,  sometimes  a  little  later,  and  may  persist  for  two  or  three 
weeks,  or  longer,  even  though  quinine  be  given. 

The  actual  number  of  parasites  found  in  the  peripheral  blood  varies 
greatly  in  different  cases.  Speaking  generally,  they  are  more  numerous 
in  the  severer  cases ;  but  it  is  to  be  remembered  that  patients  who  have 
been  energetically  treated  with  quinine  may  die  of  the  attack  with  very 
few  parasites  to  be  found  in  the  blood.  Cases  of  coma  and  hrematemesis 
are  specially  likely  to  show  this. 

Diagnosis. — The  typical  incidence  of  the  paroxysms  in  tertian  and 
quartan  fever  makes  the  diagnosis  easy.  In  irregular  or  quotidian 
fevers  the  temperature  chart  does  not  help.  The  diagnosis  can  be  made 
with  certainty  by  microscopic  examination,  and  in  any  case  should 
always  be  confirmed  by  it.  Ross  considers  that  fever  is  not  likely  to 
arise  unless  parasites  number  at  least  1  to  every  100,000  red  corpuscles, 
while  in  a  severe  case  the  proportion  of  infected  corpuscles  may  be 
12  per  cent. 


342  MALAEIA   OE  AGUE 

If  a  definite  febrile  attack  is  due  to  malaria,  there  is  little  reason 
why  the  possessor  of  a  microscope  who  knows  how  to  use  it  should  be 
unable  to  find  the  parasites.  In  stained  films  they  are  readily  recog- 
nisable, and  cannot  readily  be  mistaken  for  anything  else.  The  novice 
is  more  likely  to  imagine  he  sees  parasites  when  they  are  absent  than 
to  overlook  them  when  they  are  present.  Dust  particles,  precipitates  of 
stain,  and  spots  on  erythrocytes  due  to  imperfect  drying  are  apt  to  be 
mistaken  for  parasites.  If  a  beginner  is  in  doubt  as  to  whether  any 
given  object  is  a  parasite,  he  should  regard  it  as  something  else.  He 
is  not  likely  to  have  a  doubt  about  a  genuine  find.  Pigmented  leucocytes 
may  be  noticed. 

In  chronic  malaria  and  malarial  cachexia  parasites  may  not  be  readily 
found.  Splenic  puncture  might  reveal  them,  but  is  not  without  danger. 
Resistance  to  quinine  does  not  necessarily  exclude  malaria. 

In  difficult  cases  a  close  record  of  the  temperature,  the  splenic  enlarge- 
ment, the  differential  leucocyte  count,  the  periodic  pains,  the  general 
aspect  of  the  patient,  and  the  effect  of  quinine  must  all  be  carefully 
considered.  Urriola 1  recommends  a  careful  search  of  centrifuged  urine 
for  malarial  pigment. 

There  is  a  tendency  on  the  part  of  persons  in  this  country  who 
have  had  malaria,  and  to  a  certain  extent  on  the  part  of  their  medical 
attendants  also,  to  diagnose  as  malaria  all  febrile  conditions  occurring 
five,  ten,  or  fifteen  years  after  their  return  from  malarious  districts, 
especially  if  there  be  any  tendency  to  rigor  or  irregular  temperature. 
Mistakes  are  most  likely  to  occur  with  deep-seated  suppurative  con- 
ditions, such  as  prostatic  abscess,  pyelitis  associated  with  blocking  of 
the  ureter,  cholecystitis,  etc.  Practically  all  of  these  will  show  a 
persistent  leucocytosis  and  a  glycogen  reaction.  But  we  have  seen 
puerperal  septicaemia,  typhoid,  and  pneumonia  diagnosed  for  too  long 
as  malaria.  In  all  these  cases,  apart  from  history  and  physical  signs, 
a  proper  blood  examination  would  have  made  the  condition  evident. 

Prognosis. — In  simple  tertian  and  quartan  fevers  prognosis  is  good. 
In  quotidian  fever  due  to  tertian  or  quartan  parasites  it  is  more  serious. 
^Estivo-autumnal  fever  in  any  form  is  still  more  serious,  and  any  form 
of  pernicious  malaria  is  a  grave  condition.  Immigrants  to  a  malarial 
district  suffer  more  severely  than  natives.  Prognosis  is  worse  in  warm 
than  in  temperate  climates.  The  disease  is  more  dangerous  at  the 
extremes  of  life.  If  the  disease  has  existed  for  some  time  without  treat- 
1  La  Semaine  Med.,  4th  January  1911. 


MALABIA   OE   AGUE  343 

ment  it  is  more  serious.  Complications,  of  course,  add  to  its  gravity. 
A  very  important  factor  is  resistance  of  the  condition  to  the  action  of 
quinine  or  intolerance  of  the  patient  towards  that  drug. 

Treatment. — Prophylaxis. — Sanitary  and  engineering  works  directed 
towards  the  suppression  of  anophelines  have  practically  banished  malaria 
from  various  localities. 

The  chances  of  infection  by  mosquitoes  may  be  diminished  by  suit- 
able arrangement  of  dwelling-houses,  which  should  be  built  on  a  height 
if  possible,  and  remote  from  water  likely  to  be  a  breeding-ground  of  the 
insects.  Mosquito-proof  houses  and  mosquito  curtains  are  valuable 
protectives. 

The  prophylactic  administration  of  quinine  should  be  regularly 
carried  out  in  malarial  districts.  Various  methods  of  giving  the  quinine 
are  employed. 

Koch  recommends  15  grs.  of  quinine  on  two  consecutive  days 
every  eight  or  ten  days.  Castellani  and  Chalmers  give  5  grs.  daily 
and  an  additional  double  dose  on  Sundays.  Young  children  require 
smaller  doses,  and  euquinine  in  sweetened  milk  or  chocolate  may  be 
employed. 

Symptoms  of  cinchonism  may  arise,  and  in  that  case  the  drug  must 
be  left  off  for  a  few  days. 

Treatment  of  the  Disease. — When  an  attack  begins  the  patient  must 
go  to  bed.  In  the  cold  stage  he  should  be  kept  warm,  and  warm  drinks 
are  indicated. 

The  headache  may  be  relieved  by  the  application  of  ice  or  cooling 
lotions. 

The  patient's  garments  should  be  changed  after  the  sweating  stage, 
and  cold  or  tepid  sponging  is  grateful  and  may  induce  sleep. 

Constipation  should  be  avoided,  and  diarrhoea  should  not  be  checked 
unless  excessive.  In  delirious  and  comatose  patients  the  condition  of 
the  bladder  must  be  seen  to  regularly. 

The  diet  should  be  light  and  stimulating.  Milk,  albumin  water, 
and  meat  extracts  may  be  given  during  a  paroxysm,  and  alcoholic 
stimulants  may  be  indicated.  During  remissions  milk  puddings  and 
soups  may  be  allowed.  During  intermissions  the  patient  may  be 
allowed  ordinary  meals  of  plain  food. 

Medicinal  Treatment. — The  one  drug  which  has  a  definitely  curative 
effect  is  quinine.  It  acts  vigorously  on  the  young  forms,  less  actively  on 
the  schizonts,  but  has  much  less  effect  on  the  gametocytes,  particularly 


344  MALAEIA  OK  AGUE 

the  macrogametocyte  of  sestivo-autumnal  fever.  In  ordinary  simple 
tertian  or  quartan  attacks  a  close  of  quinine  may  be  administered  thrice 
daily,  or  the  administration  may  be  arranged  to  forestall  the  sporulation 
of  the  parasites.  It  may  be  difficult  to  get  the  patient  to  retain  quinine 
given  by  the  mouth  during  a  paroxysm.  In  such  a  case,  if  the  infection 
be  mild,  there  may  be  no  harm  in  waiting  till  the  temperature  falls  before 
beginning  the  medication.  In  severe  attacks  the  condition  is  too  urgent 
to  wait  for  a  favourable  opportunity  of  oral  administration,  and  quinine 
should  be  given  at  once  by  intramuscular  or  intravenous  injection. 

For  oral  administration  the  bisulphate  and  bihydrochloride  are  much 
more  soluble  than  the  sulphate,  and  are  therefore  to  be  preferred  unless 
the  matter  of  expense  is  a  serious  consideration.  Euquinine  is  less 
bitter  than  the  other  forms,  but  is  very  insoluble  and  expensive.  Pills, 
capsules,  and  tablets  may  be  used  with  advantage  in  mild  attacks,  but 
care  must  be  taken  to  see  that  they  are  soluble.  5  to  10  grs.  thrice 
daily  is  an  ordinary  adult  dose.  For  severe  attacks  or  in  cases  with 
gastric  derangement  intramuscular  injections  are  to  be  preferred  to 
hypodermic  administration.  Bihydrochloride  may  be  dissolved  in 
normal  saline  solution  and  carefully  sterilised,  and  15  grs.  may  be 
injected  at  a  time. 

By  far  the  most  convenient  method  is  to  purchase  the  quinine 
dissolved  and  sterilised  in  sealed  glass  bulbs  containing  a  single  dose. 
Several  such  preparations  are  on  the  market.  Ordinary  precautions  as 
regards  the  syringe  and  patient's  skin  must,  of  course,  be  taken. 

In  very  severe  infections  the  drug  should  be  administered  intra- 
venously. The  injection  should  be  made  slowly,  and  may,  if  necessary, 
be  preceded  by  a  cardiac  stimulant. 

The  dose  for  children  should  not  be  too  small.  A  child  under  a 
year  old  can  take  from  \  to  \\  grs.  every  four  hours.  Symptoms  of 
cinchonism  may  sometimes  be  diminished  or  avoided  by  the  exhibition 
of  potassium  bromide,  or  opium. 

No  other  drug  has  the  same  efficacy  as  quinine.  Good  results 
have  been  reported  from  the  application  of  X-rays  to  the  spleen.1 
Methylene  blue,  preparations  of  arsenic,  and  Donovan's  solution  may 
be  employed.  The  two  latter  are  useful  in  malarial  cachexia  and 
anaemia.  In  chronic  malaria  and  malarial  cachexia  an  important  part 
of  the  treatment  is  to  get  the  patient  out  of  the  malarial  district.  A 
sojourn  in  the  Scottish  Highlands  might  be  suggested  as  an  ideal 
change. 

1  Skinner  and  Carson,  Brit.  Med.  J  own.,  25th  February  1911. 


MALAEIA   OR  AGUE  345 

Symptomatic  Treatment. — Symptoms  may  arise  which  call  for  special 
treatment  on  general  principles.  Extreme  algid  symptoms  require  hot 
applications  to  the  body,  especially  over  the  heart. 

Cardiac  stimulants  and  oxygen  inhalations  may  be  employed. 
Great  benefit  may  follow  saline  transfusion  into  the  loose  fibrous  tissue 
at  the  lower  part  of  the  axilla. 

Hyperpyrexia  should  be  treated  with  sponging  or  cold  packs.  The 
practitioner  should  be  content  with  a  moderate  reduction  of  tempera- 
ture, since  collapse  may  follow  a  rapid  reduction.  Profuse  sweating 
may  call  for  the  administration  of  atropine  and  stimulants. 

Treatment  of  Convalescence. — The  patient  must  continue  the  use  of 
quinine  for  at  least  three  months.  Tonics  will  be  indicated,  and  iron 
and  arsenic  will  be  called  for  in  aneemia.  A  change  to  a  cool  climate 
is  always  desirable  when  circumstances  permit.  The  patient  should 
lead  a  careful,  regular  life  for  at  least  a  year  after  return  to  a  tem- 
perate climate.  Drinking  bouts,  exposure,  over-exertion,  excitement, 
etc.,  may  all  bring  on  a  recurrence. 


CHAPTER  XXXVIII 
BLACKWATER  FEVER 

Definition. — An   acute   febrile   disease   characterised    by   great   blood 
destruction  and  hemoglobinuria. 

Distribution. — The  disease  is  most  prevalent  in  tropical  Africa. 
It  occurs  in  parts  of  India  and  China.  Cases  have  also  occurred  in 
South  America  and  the  West  Indies,  and  it  is  met  with  in  Southern 
Europe. 

Etiology. — The  etiology  of  the  disease  is  not  known.  It  has  a  very 
close  association  with  malaria,  and  is  very  commonly  attributed  to  the 
malarial  parasite.  Thus  it  exists  where  there  is  severe  malaria  and 
is  not  found  where  malaria  is  absent.  Persons  attacked  have  always 
a  history  of  malaria.  Parasites  or  pigment  or  both  can  usually  be 
found  in  the  blood.  We  once  examined  a  blood  flow  which  had 
been  taken  five  hours  before  an  attack  of  blackwater  fever.  It 
showed  very  numerous  young  tertian  malarial  parasites.  Simpson 
regards  the  hemoglobinemia  as  the  expression  of  an  overflow  from 
the  normal  channel  of  excretion,  malarial  hemolysis  having  reached 
an  exceptional  degree. 

The  difficulty  in  accepting  the  purely  malarial  theory  is  its  in- 
frequency  in  cases  of  very  severe  malaria.  Moreover,  cases  occur  in 
which  pigment  and  parasites  are  absent  in  the  blood  and  may  not 
even  be  found  in  the  spleen  or  marrow  after  death. 

Another  view  is  that  the  disease  is  due  to  quinine.  There  is  no 
doubt  that  quinine  can  cause  hemolysis  and  hemoglobinuria,  but  it  is 
doubtful  if  it  can  do  so  in  healthy  persons.  Other  writers  attribute 
blackwater  fever  to  malaria  together  with  the  action  of  quinine,  and 
yet  others  postulate  a  third  factor,  such  as  renal  disease.  The  diffi- 
culty in  accepting  such  views  is  the  absence  of  blackwater  fever  in 
many  localities  where  malaria  and  presumably  the  other  conditions 
are  present. 


BLACKWATEE  FEVER  347 

The  disease  is  regarded  by  Manson  and  others  as  a  special  entity, 
and  a  variety  of  parasites,  both  animal  and  vegetable,  have  been 
suggested  as  the  causal  organism.1  Immigrants  to  an  endemic  area 
are  specially  liable  to  the  disease,  and  lowered  vitality  from  any 
cause  is  a  predisposing  factor. 

Brem2  believes  that  both  pernicious  malaria  with  hemoglobinuria 
and  blackwater  fever  (erythrocytic  h hemoglobinuria)  are  due  to  the 
action  of  a  hemolysin  produced  by  the  malarial  parasite,  generally  of 
the  estivo-autumnal  type.  He  has  prepared  extracts  of  the  parasites 
which  are  strongly  hemolytic,  and  finds  that  the  hemolysin  is  thermo- 
labile,  and  that  its  action  is  inhibited  by  the  serum  of  normal  persons. 
To  account  for  the  irregularity  of  occurrence  and  infrequency  of  black- 
water  in  malarial  infections  he  suggests  that  different  strains  of  parasites 
may  generate  hemolysins  varying  in  quantity  or  virulence,  and  that 
they  may  also  be  counteracted  by  such  factors  as  efficient  treatment  by 
quinine,  or  by  a  relative  immunity  from  previous  infections.  Or,  further, 
that  an  antihemolysin  may  be  formed,  generally  during  the  incubation 
period  of  a  malarial  infection,  when  gradually  increasing  doses  of  the 
hemolysin  are  being  liberated.  The  formation  of  this  antibody  may 
be  interfered  with  by  exhaustion  or  exposure,  especially  in  debilitated 
persons,  and  perhaps  sometimes  by  the  exhibition  of  quinine. 

Morbid  Anatomy. — The  blood  is  liquid.  The  body  is  jaundiced. 
The  liver  is  enlarged,  the  gall-bladder  full.  The  liver  cells  contain  iron- 
pigment,  and  are  fatty  or  even  necrosed  in  small  areas.  There  may  be 
thrombi  in  the  sublobular  veins.  The  intestines  are  usually  congested. 
The  kidneys  are  enlarged  and  dark  coloured.  The  tubular  epithelium 
is  degenerated,  and  the  tubes  contain  granular  material  staining  as 
hemoglobin.  The  glomeruli  contain  granular  matter,  and  there  is 
proliferation  of  capsular  endothelium.  It  has  been  suggested  that 
the  hemolysis  occurs  in  the  kidneys.  The  bone-marrow  may  show 
gelatinous  degeneration. 

Symptoms. — There  may  be  prodromal  symptoms,  including  lassitude, 
loss  of  appetite,  pains,  restlessness,  and  slight  jaundice.     The  attack 

1  Cell  inclusions  and  protozoal-like  structures  have  been  described  by  Leishman, 
Journ.  of  Trop.  Med.,  16th  December  1912  and  1st  January  1913  ;  Coles,  Lancet,  3rd 
May  1913  ;  and  Low  and  Wenyon,  Journ.  of  Troy.  Med.,  2nd  June  1913. 

2  Arch,  of  Intern.  Med.,  1912. 


348  BLACKWATER  FEVER 

is  ushered  in  by  a  feeling  of  chilliness  and  shivering.  The  tempera- 
ture rises  to  103°  or  104°  F.  There  is  headache,  pain  in  the  back  and 
limbs,  and  great  weakness.  There  is  nausea  and  bilious  vomiting, 
thirst,  and  constipation.  Occasionally  large  quantities  of  blood  are 
passed  by  the  bowel.  The  liver  and  spleen  are  enlarged  and  tender. 
The  pulse  is  feeble  and  rapid.  The  skin  is  hot  and  dry,  and  rapidly 
assumes  a  yellow  colour.  The  conjunctivae  are  yellow.  The  urine 
may  appear  normal  at  first,  but  soon  becomes  dark  in  colour.  Occa- 
sionally the  dark  urine  is  the  first  symptom  noticed.  The  actual 
colour  may  be  yellowish-brown,  red,  or  black.  Diluted  specimens 
give  the  spectrum  of  oxyhemoglobin,  sometimes  of  inethaemoglobin 
after  standing.  The  reaction  is  faintly  alkaline.  The  specific  gravity 
is  often  low.  A  sediment  of  broken-down  red  corpuscles  and  blood- 
pigment  appears  after  the  urine  has  stood.  The  presence  of  urobilin 
can  be  made  out  by  acidulating  the  urine  with  acetic  acid,  extracting 
the  pigment  with  amylic  alcohol,  and  examining  with  the  spectroscope. 
Bile  pigments  are  sometimes  present,  and  there  is  usually  albumin  and 
globulin.  There  may  be  symptoms  of  uraemia.  Coma  and  delirium 
are  not  uncommon.  After  a  few  hours  symptoms  may  lessen.  Per- 
spiration begins,  the  temperature  falls,  the  urine  clears,  and  recovery 
may  take  place.  On  the  other  hand  hyperpyrexia,  coma,  and  death 
may  occur.  Even  after  a  remission  the  temperature  usually  rises 
again  with  a  return  of  symptoms,  and  a  succession  of  such  relapses 
may  cause  death  by  exhaustion.  After  the  attack  the  patient  is  very 
weak.  Convalescence  is  prolonged  and  kidney  symptoms  are  apt  to 
arise. 

The  Blood  Changes. — The  blood  is  thin  and  watery.  There  is 
haemoglobinaemia  and  cholaemia.  The  red  cells  are  greatly  reduced  in 
number.  The  haemoglobin  is  reduced  but  the  coloured  plasma  leads  to 
a  fairly  high  colour  index.  Many  of  the  red  corpuscles  are  represented 
by  mere  shadows  or  fragments.  At  a  later  stage  polychromasia  and 
the  presence  of  nucleated  red  cells  may  be  found.  Malarial  parasites 
may  be  seen.  During  the  fever  there  is  leucocytosis  due  to  increased 
polymorphs.  During  remissions  there  is  leucopenia,  with  an  increase 
of  large  mononuclear  cells.     Malarial  pigment  may  be  noticed. 

Prognosis. — The  prognosis  varies  in  different  epidemics  and  in 
different  districts.     Mortality  ranges  from  4  to  50  per  cent. 


BLACKWATEE   FEVER  349 

Treatment. — Prophylaxis. — In  the  present  state  of  our  knowledge 
prophylactic  measures  directed  against  malaria  probably  apply  to  this 
disease.  A  person  who  has  once  had  blackwater  fever  should  not 
remain  in  the  tropics.  This  rule  has  been  broken  with  apparent 
impunity,  but  the  risks  of  disregarding  it  are  very  great. 

Treatment  of  the  Disease. — The  patient  should  be  in  bed.  The  diet 
should  be  liquid.  Milk,  whey,  albumin  water,  gruel,  etc.,  should  be  the 
main  items.     Meat  extracts  are  better  avoided. 

An  attempt  should  be  made  to  flush  the  kidneys.  Large  quantities 
of  soda  water,  barley  water,  etc.,  should  be  taken  by  the  mouth  whenever 
possible.  If  gastric  irritability  does  not  permit  of  this,  saline  enemata 
or  saline  transfusion  into  subcutaneous  tissue  may  be  carried  out. 
Cardiac  stimulants  are  indicated.  Chlorides,  especially  calcium  chloride, 
have  been  recommended.  If  malaria  parasites  are  present  quinine  should 
be  administered  in  the  form  of  bihydrochloride.  The  sulphate  should  be 
avoided  because  of  its  hsemolytic  action. 

Ureemie  symptoms  may  be  treated  on  the  usual  lines,  and  a  variety 
of  symptoms  may  call  for  special  attention. 

Convalescence  requires  general  tonic  treatment  and  special  treatment 
for  ansemia.  The  diet  should  be  restricted  in  view  of  probable  damage 
to  the  kidney.  As  soon  as  possible  the  patient  should  remove  to  a 
temperate  climate. 


CHAPTER  XXXIX 

KALA-AZAE 

Definition. — A  disease  caused  by  a  protozoal  organism  in  the  spleen 
and  other  organs  and  occasionally  in  the  blood,  characterised  by  long- 
continued  fever,  anaemia  and  debility,  and  enlargement  of  the  liver  and 
spleen,  usually  resulting  in  death. 

Distribution. — The  disease  is  endemic  in  Assam  and  to  a  less  extent 
in  Lower  Bengal.  Large  epidemics  are  frequent.  Cases  have  occurred 
in  practically  all  parts  of  India,  in  the  Soudan,  and  have  been  reported 
in  other  parts  of  the  world,  but  in  some  instances  it  is  uncertain  whether 
the  disease  has  been  endemic  or  imported. 

Etiology. — There  is  now  little  doubt  that  the  infecting  agent  is  the 
Eastern  bed-bug,  Cimex  rotundatus,  whose  bite  introduces  a  parasite, 
the  Leishman- Donovan  body. 

Patton  has  recently  followed  out  the  whole  cycle  of  development  in 
bugs,  both  Cimex  rotundatus  and  C.  lectularius  (the  European  bed-bug), 
by  feeding  them  on  a  case  which  contained  the  parasites  in  the  circulating 
blood.  He  was  able  to  trace  the  parasite  from  its  unchanged  state  in 
leucocytes,  through  the  flagellate  stage,  to  the  rounding  up  in  the  post- 
flagellate  form.  If  bugs  containing  developing  forms  are  fed  on  another 
case  (a  monkey  suffering  from  kala-azar  was  used),  the  flagellating 
forms  are  destroyed  within  twenty-four  hours,  but  if  they  are  not  fed 
again,  development  goes  on  and  is  completed  in  C.  rotundatus  in  from 
ten  to  twelve  days  after  the  single  feed.  This  interesting  fact  prob- 
ably prevents  many  bugs  from  becoming  infective,  and  prevents  the 
spread  of  the  disease  outside  its  endemic  areas.  Patton  found  also 
that  development  took  place  as  easily  in  C.  lectularius  as  in  C. 
rotundatus,  and  in  a  rather  shorter  time — from  seven  to  ten  days — 
and  he  considers  that  this  is  the  probable  explanation  of  the  infantile 
kala-azar  (gr.v.).  Seen  in  fresh  unstained  preparations  the  parasites 
appear  as  refractile  colourless  bodies  of  indefinite  outline,  somewhat 
resembling  blood-plates.     Stained  by  Leishman's  method  they  appear  as 


KALA-AZAE  351 

sharply-defined  round  or  oval  bodies,  measuring  from  2"5  x  1*5  to  3*5  x  2  p. 
The  body  of  the  parasite  stains  a  faint  blue  colour.  It  contains  two 
masses  of  chromatin,  one  large  and  round,  the  nucleus,  the  other  smaller, 
often  rod-shaped  and  more  deeply  stained,  the  blepharoplast.  These 
masses  often  lie  at  opposite  ends  of  the  smaller  diameter  of  the  parasite, 
with  the  long  axis  of  the  smaller  at  right  angles  to  that  of  the  larger. 

The  parasites  can  be  cultivated  outside  the  body.  They  develop  in 
citratecl  blood  rendered  acid  by  the  addition  of  citric  acid.  The  optimum 
temperature  for  their  cultivation  is  20  to  22°  C.  In  cultures  flagellate 
forms  develop,  and  this  fact  led  to  the  suggestion  that  the  organism 
was  a  phase  in  the  life-history  of  a  trypanosome.  No  undulating 
membrane,  however,  develops,  and  the  flagellum  is  at  the  blunt 
posterior  end  of  the  parasite  next  the  micronucleus.  It  is  probably 
a  herpetomonas. 


A 


Fig.  28. 

a.  Stages  in  the  development  of  trypanosome.    b.  Stages  in  the  development  of  the  Leishman  body. 

Morbid  Anatomy. — There  is  great  enlargement  of  the  spleen  and 
liver,  inflammation  of  the  large  intestine,  and  often  effusion  of  serous 
fluid  and  oedema.  The  splenic  enlargement  is  massive.  Perisplenitis 
is  usually  absent.  The  spleen  substance  is  firm  but  friable.  On  section 
the  surface  is  dark  red.  On  microscopic  examination  there  is  great 
dilatation  of  the  sinuses  and  atrophy  of  the  Malpighian  bodies. 
Scattered  throughout  the  pulp  are  generally  enormous  numbers  of  the 
parasites.  They  are  found  chiefly  in  the  endothelial  cells  but  also  in 
the  large  lymphocytes  and  in  smaller  numbers  in  the  polymorphs. 
They  are  not  found  in  the  Malpighian  corpuscles. 

The  enlargement  of  the  liver  is  not  so  great  as  that  of  the  spleen. 
The  organ  is  firm  but  friable.  There  is  usually  a  good  deal  of  fatty 
change  and  a  considerable  deposition  of  iron-containing  pigment.    There 


352  KALA-AZAE 

is  some  proliferation  of  endothelial  cells.  Parasites  are  numerous  in 
endothelial  cells  and  in  free  mononuclear  cells,  but  do  not  occur  in 
the  liver  cells, 

The  large  intestine  is  often  inflamed  and  thickened  and  may  be 
ulcerated.  The  small  intestine  may  show  the  same  changes  in  a  minor 
degree. 

A  few  parasites  may  be  found  in  the  endothelium  of  capillaries. 

In  uncomplicated  cases  the  other  organs  are  usually  healthy. 
Parasites  are  numerous  in  the  bone-marrow,  chiefly  in  the  large 
lymphocytes,  but  there  are  also  a  few  in  the  myelocytes.  Parasites  are 
also  found  in  small  numbers  in  the  capillaries  of  most  of  the  other 
organs  and  in  the  lymph  glands,  particularly  those  of  the  mesentery. 

Symptoms. — The  incubation  period  is  not  known,  but  symptoms 
have  developed  in  patients  months  after  they  had  left  an  infected  area. 
The  symptoms  of  the  disease  often  develop  in  three  stages — the  initial 
fever,  secondary  fever,  and  cachexia.  These  stages  are  not  always 
sharply  defined. 

First  Stage. — Sometimes  the  onset  of  the  disease  is  very  insidious, 
but  perhaps  more  frequently  it  begins  with  rigors  or  chills  which  may 
recur  daily.  The  fever  is  usually  remittent,  but  later  becomes  inter- 
mittent. In  most  cases  the  rise  of  temperature  takes  place  in  the 
evening,  but  in  some  cases  there  may  be  two  or  even  three  daily  exacerba- 
tions of  fever.  After  some  days  the  spleen  becomes  enlarged  and  tender 
and  the  liver  shows  the  same  changes  in  a  less  degree.  Anaemia  and 
wasting  are  early  features.  The  skin  may  become  darker,  and  headache 
is  sometimes  complained  of.      The  appetite  as  a  rule  remains  good. 

This  stage  may  last  for  from  ten  to  sixty  days,  commonly  about 
a  month. 

Second  Stage. — There  may  now  be  a  short  interval,  during  which  the 
patient  appears  to  recover,  but  this  feature  is  often  absent.  The  patient 
then  shows  a  low  fever  of  very  varying  type  for  weeks  or  months  or 
even  a  year.  The  liver  and  spleen  continue  to  enlarge,  the  latter 
enormously. 

Third  Stage. — There  is  now  very  marked  cachexia,  with  great 
emaciation  and  weakness.  The  temperature  is  often  subnormal.  The 
appetite  is  ravenous  in  many  cases.  Diarrhoea  is  generally  a  prominent 
symptom,  and  is  perhaps  the  most  frequent  cause  of  death.  The  end 
is  often  brought  about  by  asthenia  or  by  a  complication  such  as 
pneumonia  or  cancrum  oris. 


KALA-AZAR  353 

The  total  duration  varies  from  a  few  months  to  two  years  and  is 
usually  rather  over  a  year.     Atypical  cases  are  fairly  common. 

Blood  Changes. — Anaemia  is  a  constant  feature.  The  number  of  red 
and  white  corpuscles  may  be  said  to  diminish  progressively  throughout 
the  disease.  The  red  cells  are  very  commonly  found  to  number  3,000,000 
per  c.mm.  The  haemoglobin  is  rather  more  than  correspondingly 
diminished.     The  usual  features  of  secondary  anaemia  are  present. 

White  Cells. — These  are  diminished,  and  some  remarkably  low  counts 
have  been  recorded.  Eeduction  to  3000  is  common,  but  the  number 
may  fall  as  low  as  500  per  c.mm. 

The  decrease  chiefly  affects  the  polymorphs,  so  that  there  is  a 
considerable  relative  lymphocytosis,  especially  of  the  large  variety. 
Polymorphs  are  often  reduced  to  40  or  50  per  cent.  Small  lympho- 
cytes comprise  20  to  30  and  large  lymphocytes  15  to  20. 

Rogers  states  that  the  ratio  of  white  to  red  cells  falls  as  low  as  1  to 
1000  in  all  uncomplicated  progressive  cases,  and  holds  that  a  reduction 
of  the  ratio  to  1  to  1500  is  diagnostic  of  kala-azar  from  other  Indian 
fevers. 

The  parasite  occurs  only  sparingly  in  the  blood,  and  is  said  to  be 
found  more  easily  when  the  temperature  is  high.  It  is  contained  in 
the  large  lymphocytes  and  polymorphonuclear  cells. 

In  order  to  find  the  parasite  a  large  number  of  leucocytes  must  be 
brought  under  review,  either  by  examining  the  edges  of  thick  films,  or 
by  making  films  from  the  leucocyte  layer  of  centrifuged  blood.  It  is 
the  exception  rather  than  the  rule  to  find  the  parasite  in  peripheral 
blood. 

Malaria  parasites  or  pigment  may  be  present  as  a  complication. 

Diagnosis. — At  the  onset  of  the  disease  the  diagnosis  is  attended  with 
very  great  difficulty.  It  may  present  a  close  resemblance  to  typhoid 
or  malaria.  In  one  case  which  was  under  our  care  the  difficulty  of 
diagnosis  from  typhoid  in  the  early  stage  was  increased  by  the  presence 
of  a  positive  Widal  reaction.  Even  in  the  later  stages  it  may  be  difficult 
to  differentiate  the  disease  from  malarial  cachexia,  and  the  two  conditions 
may  co -exist. 

The  only  certain  diagnostic  is  the  demonstration  of  the  parasite,  and 
it  is  often  impossible  to  find  it  in  the  peripheral  blood.  It  is,  however, 
readily  obtained  by  puncture  of  the  liver  or  spleen.  There  is  consider- 
able risk  of  even  fatal  haemorrhage  in  the  case  of  the  latter  procedure 

23 


354  KALA-AZAE 

in  kala-azar,  and  liver  puncture  is  to  be  preferred.  This  measure  is 
carried  out  by  means  of  a  sterile  syringe,  which  must  be  dry,  as  moisture 
may  disintegrate  the  parasites.  The  skin  is  sterilised  and  the  needle  is 
plunged  deeply  into  the  liver  with  a  slight  rotatory  movement.  The 
syringe  should  follow  the  respiratory  movements  of  the  liver.  After 
about  a  minute  gentle  aspiration  is  effected.  It  is  not  desirable  to 
obtain  much  blood,  as  it  only  dilutes  the  lymph  containing  the  parasites. 
The  fluid  thus  obtained  is  spread  into  a  series  of  thin  films,  which  may 
be  stained  by  Leishman's  method.  The  number  of  parasites  so  obtained 
varies  very  greatly.  They  may  be  free  or  contained  in  cells  or 
embedded  in  a  matrix.  This  matrix  is  not  seen  in  smears  made 
from  organs  after  death  and  is  not  seen  in  sections.  It  is  probably 
due  to  the  disintegration  of  phagocytic  cells  which  have  taken  up 
the  parasites. 

Prognosis. — Authentic  cases  of  recovery  are  on  record,  but  the 
mortality  is  very  high,  probably  not  less  than  96  to  98  per  cent. 

Treatment. — Prophylactic  treatment  appears  to  consist  in  the  avoid- 
ance of  too  close  an  acquaintanceship  with  Cimex  rotundatus.  Price 
and  Eogers  give  an  interesting  account  of  the  effect  of  a  removal  of 
Coolie  lines  from  an  infected  area.  The  new  huts  were  only  400  yards 
from  those  severely  infected,  yet  no  case  had  occurred  in  the  new  lines 
during  sixteen  years.  The  treatment  of  the  disease  is  unsatisfactory. 
Cures  have  followed  the  use  of  atoxyl.  Quinine  in  large  doses  has  been 
said  to  do  good.  Arsenic,  salicylates,  and  drugs  calculated  to  increase  the 
number  of  leucocytes  have  all  been  tried.  Symptomatic  treatment  is  of 
course  called  for,  and  in  the  case  of  Europeans  removal  to  a  temperate 
climate  may  do  good  and  will  certainly  add  to  the  patient's  comfort. 

Literature 

For  the  history  of  the  discovery  of  the  parasite  and  its  characters,  see 
Eogers,  Proc.  Boy.  Soc,  1906,  284,  and  Brit.  Med.  Journ.,  23rd  February, 
2nd  and  9th  March  1907  ;  Price  and  Eogers,  Brit.  Med.  Journ.,  7th  February 
1914. 

Infantile  Kala-Azar 

This  disease,  met  with  in  Southern  Italy,  Sicily,  Malta,  and  North 
Africa,  appears  to  be  identical  with  Indian  kala-azar. 

Etiology. — The  disease  is  due  to  the  parasite  Leishmania  infantum 


KALA-AZAR  355 

(Nicolle),  which  is  similar  to  the  Leishman-Donovan  body.  It  has  been 
inoculated  into  monkeys  and  dogs.  Nicolle  regards  the  dog  as  a  reservoir 
of  the  virus,  and  considers  that  its  ectoparasites,  such  as  fleas,  are  the 
transmitting  agents  to  human  subjects,  but  Patton's  recent  observations 
on  bugs  (p.  350)  may  cause  this  view  to  be  modified. 

Symptoms. — The  disease  cannot  be  distinguished  from  ordinary 
kala-azar,  except  that  it  usually  affects  children  from  one  to  six  years 
of  age.  It  generally  begins  with  irregular  attacks  of  fever.  There  is 
progressive  anaemia,  and  polymorphs  are  diminished.  The  liver  and 
spleen  are  enlarged,  and  there  is  great  emaciation  and  sometimes 
cutaneous  haemorrhages.  Duration  is  from  a  few  months  to  several 
years.     The  outcome  is  usually  fatal. 

Diagnosis. — The  diagnosis  is  made  by  finding  the  parasite  by  liver 
or  splenic  puncture.  Pianese  recommends  puncture  of  the  superior  end 
of  the  tibia  and  examination  of  the  marrow  for  parasites.  Cretien1 
has  found  the  parasite  in  mucous  flakes  in  the  fasces. 

Treatment. — Treatment  is  unsatisfactory,  and  is  on  the  same  lines 
as  that  of  Indian  kala-azar. 

1  Brit.  Med,  Journ.,  28th  January  1911. 


CHAPTER  XL 

TRYPANOSOMIASIS 

The  occurrence  of  trypanosomes  in  the  blood  of  fish  and  amphibians 
has  been  known  for  over  sixty  years,  and  numerous  varieties  have  been 
described  in  these  animals  as  well  as  in  reptiles,  birds,  and  some 
invertebrates.  It  is  only  within  recent  years  that  their  importance 
in  mammalia  has  been  recognised,  and  in  1901  they  were  discovered 
to  be  pathogenic  to  man. 

Characters. — Trypanosomes  are  fusiform  in  shape  and  have  a  longi- 
tudinal membrane  along  the  side.  The  thickened  border  of  this 
membrane  ends  posteriorly  in  a  small  mass  of  chromatin,  the  blepharo- 
plast  or  centrosome,  and  is  prolonged  anteriorly  into  a  free  flagellum. 
The  nucleus  is  generally  anterior.  The  organisms  are  actively  motile. 
Reproduction  takes  place  by  simple  division.  The  parasites  divide 
longitudinally  and  unequally.  "Whether  previous  conjugation  occurs 
is  not  determined  with  certainty. 

Trypanosomes  can  be  cultivated  on  artificial  media.  Sterile 
defibrinated  blood  is  added  to  ordinary  nutrient  agar  after  cooling 
to  50°  C.  Unaltered  haemoglobin  seems  to  be  essential.  Abundance 
of  oxygen  and  moisture  are  necessary.  Cultures  at  room  temperature 
retain  their  vitality  for  months.  In  the  incubator  growth  is  more 
rapid,  reaching  a  maximum  in  eight  to  twelve  days,  death  occurring  in 
three  weeks. 

The  following  varieties  are  of  special  importance : — 

T.  Leivisi. — This  parasite  infects  rats  in  all  parts  of  the  world.  In 
London  25  per  cent,  were  found  to  be  affected,  in  Bordeaux  100  per 
cent.  The  adult  is  27  to  28  ^  in  length  including  the  flagellum,  1*5 
to  2  ft  wide.  The  parasite  appears  to  be  harmless  in  adults  but  may 
cause  fatal  disease  in  young  rats.  Its  invertebrate  host  is  the  flea,  but 
it  can  also  live  in  the  louse  and  bed-bug. 

T.  Cuniculi. — This  parasite  has  been  found  in  the  blood  of  wild  and 
tame  rabbits.  It  is  morphologically  identical  with  T.  Lewisi,  but  rats 
are  refractory  to  inoculation  with  this  form. 

356 


TRYPANOSOMIASIS  357 

T.  Brucei. — This  parasite  causes  nagana,  the  "  fly-disease  "  of  South 
Africa.  It  also  occurs  in  Uganda.  The  disease  is  rapidly  fatal  in 
horses,  and  produces  a  more  chronic  disease  in  cattle,  sheep,  and  goats. 
It  causes  death  in  rats  in  from  three  to  five  days,  and  can  be 
inoculated  into  practically  all  the  laboratory  animals.  It  has  a 
shorter  flagellum  and  is  less  motile  than  T.  Lewisi.  It  varies  con- 
siderably in  length. 

T.  Evansi. — This  trypanosome  occurs  in  India,  North  America,  and 
Australia.  It  gives  rise  to  the  disease  known  in  India  as  "  surra."  It 
is  fatal  chiefly  to  horses  but  also  affects  cattle.  Length  is  25  to  35  /*, 
and  the  flagellum  is  very  long. 

T.  Equiperdum. — The  disease  caused  by  this  organism  is  "  dourine," 
which  affects  horses.  It  occurs  in  continental  Europe,  the  East,  and 
the  United  States.  T.  Equiperdum  is  25  to  28  fi  in  length,  protoplasm 
is  very  feebly  coloured,  and  granules  are  absent.  The  disease  is  usually 
spread  by  coitus,  rarely  by  biting  flies. 

T.  JSquinum  causes  the  "  mal-de-Caderas  "  of  South  America.  It  is 
fatal  to  horses. 

T.  Theileri. — This  trypanosome  infects  cattle  in  the  Transvaal. 
There  are  large  forms  up  to  70  p  and  smaller  from  25  to  30  fi  in 
length. 

T.  Pecorum  causes  disease  in  horses  and  cattle,  and  is  widely 
distributed  in  Africa.  It  is  pathogenic  to  most  laboratory  animals 
but  not  to  guinea-pigs. 

T.  Vivax. — This  easily  recognisable  species  gives  rise  to  a  fatal 
disease  of  cattle  in  Uganda.  The  carrier  is  probably  Glossina 
palpalis. 

T.  Nanum  is  a  small  trypanosome,  pathogenic  to  cattle. 

Human  Trypanosomiasis — A.  Sleeping  Sickness 

A  disease  caused  by  the  presence  in  the  blood  and  cerebro-spinal 
fluid  of  T.  Gambiense,  characterised  by  fever,  anaemia,  enlargement  of 
lymphatic  glands  and  spleen,  and  cerebral  symptoms,  and  terminating 
fatally. 

Distribution. — The  disease  is  limited  to  persons  who  have  resided 
in  South  and  Tropical  Africa.  It  is  specially  prevalent  throughout  the 
Congo,  and  within  recent  years  has  appeared  in  the  neighbourhood  of 
Victoria  Nyanza. 


358  TKYPANOSOMIASIS 

Etiology. — The  disease  is  caused  by  the  bite  of  a  tsetse-fly.  The 
chief  carrier  is  Glossina  palpalis,  but  G.  morsitans  and  possibly  other 
varieties  of  Glossina  may  also  be  vectors.  The  fly,  in  some  way  not 
understood,  infects  its  victim  with  T.  Gambiense.  In  some  cases  there 
is  direct  transmission,  the  fly  feeding  on  an  infected  animal  and  immedi- 
ately afterwards  feeding  on  another  susceptible  animal.  The  power  of 
transmission  is  soon  lost,  but  a  certain  .-proportion  of  flies  again  become 
infective  twenty-eight  days  after  they  have  fed  on  an  infected  animal. 
They  remain  infective  for  at  least  ninety-six  days.  From  the  eighth 
to  the  forty-fourth  day  after  an  infective  feed  a  developing  form  of 
trypanosome  can  be  found  in  the  gut  of  the  fly.  The  renewed  infectivity 
of  the  fly  seems  to  be  coincident  with  an  invasion  of  its  salivary  glands 
by  trypanosomes. 

Morbid  Anatomy. — Little  is  known  of  the  pathological  changes  in 
the  early  stages  of  the  disease  in  man.  In  lower  animals  the  chief 
conditions  are  congestion  of  viscera,  enlargement  of  lymph  glands  and 
spleen,  and  sometimes  congestion  of  the  brain  and  cord. 

In  sleeping  sickness  there  is  accumulation  of  round  cells  in  the 
perivascular  spaces  of  the  capillaries  of  the  brain  and  spinal  cord. 
The  lymph  glands  are  often  hemorrhagic  and  contain  pigment.  The 
spleen  is  also  pigmented.  The  bone-marrow  commonly  shows  gelatinous 
degeneration.  Evidence  of  secondary  bacterial  infection  of  the  brain 
is  often  found. 

T.  Gambiense  measures  17  to  25  //.  including  the  flagellum,  which 
averages  6  or  7  ^  Its  breadth  is  1*5  to  2  p.  The  protoplasm  contains 
chromatic  granules — chromatoph  ores. 

Symptoms. — The  incubation  period  in  monkeys  is  about  fourteen 
days.  The  onset  in  man  is  associated  with  fever,  often  of  a  very 
irregular  type.  Some  of  the  lymphatic  glands,  particularly  those  at 
the  back  of  the  neck,  are  slightly  enlarged  and  tender.  In  Europeans 
there  is  usually  a  rash  of  very  evanescent  character,  generally  taking 
the  form  of  erythematous  rings.  They  are  chiefly  to  be  seen  on  the 
abdomen  and  chest.  There  is  progressive  weakness  and  loss  of  flesh. 
There  may  be  muscular  tremors  and  the  muscles  become  tender.  The 
heart  is  rapid  and  excitable.  The  appetite  often  remains  good.  After 
some  weeks  or  months  the  fever  may  subside,  the  patient  feels  better, 
and  trypanosomes  diminish  in  the  peripheral  blood,  and  indeed  their 
presence  may  only  be  discovered  by  inoculating  2  c.c.  or  more  of  the 


TKYPANOSOMIASIS  359 

blood  into  monkeys.  This  stage  may  last  for  some  years.  Sooner  or 
later  the  terminal  cerebral  symptoms  make  their  appearance.  The  first 
indication  of  their  onset  may  be  a  series  of  epileptiform  convulsions, 
or  a  rapidly  fatal  coma  may  supervene.  The  usual  course,  however, 
is  the  onset  of  an  overpowering  lethargy.  The  patient  is  always 
drowsy,  and  may  fall  asleep  during  meals  or  any  active  occupation. 
There  is  mental  irritability  and  incapacity.  There  is  progressive 
weakness  and  emaciation  even  when  the  patient  is  regularly  fed. 
Sometimes  diarrhoea  is  a  prominent  terminal  symptom,  but  death 
usually  follows  a  more  or  less  prolonged  period  of  coma. 

The  Blood. — Anosmia  is  an  early  symptom,  and  as  the  disease 
advances  it  may  become  extreme.  Eed  cell  counts  of  little  over  a 
million  per  cubic  millimetre  have  often  been  noted.  White  cells 
show  little  disturbance  in  actual  number  but  their  proportions  are 
altered.  There  is  usually  an  increase  of  lymphocytes,  particularly 
the  large  mononuclear  variety.  Polymorphs  are  correspondingly 
diminished.  Eosinophils  are  increased,  in  some  cases  even  to  the 
extent  of  25  per  cent.  A  slight  increase  of  basophils  has  once  or 
twice  been  noted. 

Diagnosis. — The  disease  is  only  diagnosed  with  certainty  by  the 
finding  of  trypanosomes  either  directly  or  by  inoculation.  In  the 
early  stage  the  parasites  may  be  found  with  comparative  ease  in  the 
peripheral  blood.  Greater  certainty  of  finding  the  trypanosomes  may 
be  attained  by  withdrawing  a  few  cubic  centimetres  of  blood,  mixing 
them  with  an  equal  quantity  of  1  per  cent,  sodium  citrate  solution, 
and  centrifuging.  The  trypanosomes  are  to  be  sought  in  the  leucocyte 
layer.  Aspiration  of  fluid  from  one  of  the  enlarged  glands  will  often 
reveal  the  presence  of  parasites.  In  the  later  stage  the  parasites  are 
to  be  found  in  the  cerebro-spinal  fluid.  Some  of  the  fluid  is  withdrawn 
by  lumbar  puncture  and  centrifuged.  In  some  cases  the  parasites  are 
never  numerous,  and  a  negative  diagnosis  can  only  be  made  after 
inoculation  experiments  have  failed. 

The  trypanosomes  are  readily  seen  in  fresh  blood  owing  to  their 
mobility.     They  are  stained  by  Leishman's  method. 

Treatment. — In  the  case  of  a  disease  whose  mortality  is  probably 
not  less  than  100  per  cent,  it  is  of  special  importance  that  preventive 
measures  should  be  adopted.    The  prophylaxis  of  trypanosome  disease, 


360  TRYPANOSOMIASIS 

however,  opens  up  very  large  questions  of  administration  rather  than  of 
personal  regime,  and  we  must  refer  readers  to  works  on  tropical  medicine 
for  their  discussion.  In  the  case  of  the  individual  the  prophylaxis  of 
trypanosomiasis  resolves  itself  into  the  avoidance  of  a  bite  from  a  tsetse- 
fly.  The  treatment  of  the  disease  is  unsatisfactory.  Preparations  of 
arsenic  appear  to  do  some  good.  Atoxyl  and  its  congeners  have  been 
largely  used,  but  large  doses  may  cause  blindness,  and  a  prolonged 
course  seems  to  lead  to  the  acquisition  of  immunity  on  the  part  of  the 
trypanosomes.  A  combined  treatment  by  atoxyl  and  antimony  or 
mercury  seems  to  be  of  some  benefit.  Atoxyl  may  be  given  intra- 
muscularly in  doses  of  ten  grains  on  two  consecutive  days  at  intervals 
of  fourteen  days  for  a  period  of  two  months.  In  the  intervals  dilute 
solutions  of  antimony  or  mercury  may  be  employed.  Salvarsan  does 
not  appear  to  do  good. 

B.  Rhodesian  Trypanosomiasis 

In  1910  Stephens  and  Pantham x  described  a  case  of  sleeping  sick- 
ness in  a  patient  who  had  contracted  the  disease  in  Rhodesia,  where 
G.  palpalis  is  not  found.  The  carrier  is  G.  morsitans,  which,  unfor- 
tunately, is  distributed  over  a  wide  range  of  country,  and  is  not  limited 
to  the  neighbourhood  of  watercourses,  as  is  G.  palpalis.  The  trypano- 
some,  T.  Bhodesiense,  shows  no  very  essential  difference  from  T.  Gambi- 
ense,  but  its  nucleus  is  often  situated  posteriorly  near  the  blepharoplast, 
and  its  anterior  end  is  longer  in  many  instances.  T.  Rhodesiense  shows 
a  greater  virulence  than  T.  Gambiense  when  inoculated  into  animals. 
The  course  in  man  is  more  rapid,  and  the  condition  is  not  amenable 
to  any  treatment. 

C.  South  American  Trypanosomiasis 

In  1909  Chagas  found  a  trypanosome  in  the  blood  of  a  child  in 
Brazil.  The  trypanosome  is  T.  cruzi,  and  is  capable  of  being  trans- 
mitted by  a  bug,  Conorhinus  megistus,  to  man  and  domestic  animals. 
Blacklock  has  shown  that  T.  cruzi  is  also  capable  of  living  and  multi- 
plying in  Cimex  lectularius.  The  parasites  found  in  the  bed-bug  are 
infective  on  inoculation  as  early  as  twenty-one  hours  and  as  late  as 
seventy-seven  days  after  the  infecting  feed.  Many  different  forms  of 
the  parasite  occur  in  the  bug,  but  it  is  not  known  which  one  causes 
1  Proc.  Roy.  Soc,  B.  83,  1910,  28. 


TRYPANOSOMIASIS  361 

infection  in  the  vertebrate  host.  Blaeklock  found  that  transmission  to 
healthy  animals  by  feeding  infected  bed-bugs  on  them  was  of  very 
rare  occurrence,  but  Chagas  has  successfully  inoculated  marmosets,  dogs, 
cats,  guinea-pigs,  and  rabbits  by  allowing  the  infected  Conorhinus  to  bite 
them.  He  has  also  cultivated  the  trypanosome  on  blood-agar.  Three 
forms  are  found  in  the  blood,  one  with  a  large  nucleus  and  a  terminal 
micronucleus,  a  second  narrower  with  oval  nucleus,  and  a  third  with  a 
long  nucleus. 

Symptoms. — There  are  attacks  of  remittent  and  intermittent  fever, 
oedema,  glandular  enlargements,  splenic  hypertrophy,  aneemia,  and 
wasting.  In  children  there  is  maldevelopment.  The  trypanosomes 
occur  in  the  blood  only  during  pyrexia.  Some  cases  terminate  fatally, 
the  majority  pass  into  a  condition  of  chronic  illness. 

Literature 

Chagas,  Arch.f.  Schiffs-io.  Tropen-Hygiene,  1909  ;  Brazil  Medico.,  22nd  April 
1909  ;  Bulletin  cle  la  Soc.  cle  Path.  Exotique,  1909 ;  Blaeklock,  Brit.  Med.  Journ., 
25th  April  1914. 


CHAPTEE  XLI 
DISEASES   DUE   TO   SPIROCHETES   IN  THE   BLOOD 

Several  species  of  pathogenic  spirochetes  are  known.  These  include 
Spirochteta  Obermeieri,  the  cause  of  relapsing  fever;  S.  Duttoni,  the 
cause  of  African  tick  fever;  S.  Theileri,  which  affects  cattle  in  South 
Africa;  S.  Gallinarum,  affecting  fowls  in  Brazil  and  the  Soudan;  S. 
Granulosa,  found  in  Soudanese  fowls ;  S.  Anserina,  the  cause  of  disease 
in  geese ;  and  the  spirochseta  pallida  of  syphilis. 

These  organisms  all  cause  fever,  and  are  found  in  the  peripheral 
blood.  It  has  been  demonstrated  that  certain  of  them  are  conveyed 
by  the  bite  of  ticks.  S.  Duttoni  is  transmitted  by  Ornithodorus 
moubata,  S.  Theileri  by  Boophilus  decoloratus,  and  S.  Gallinarum  by 
Argus  persicus. 

There  seems  to  be  a  definite  though  slight  distinction  between  the 
European  relapsing  fever  due  to  S.  Obermeieri  and  African  tick  fever 
due  to  S.  Duttoni.  Owing  to  still  slighter  differences  it  has  been 
suggested  that  there  is  a  North  African  type  due  to  S.  Berbera,  an 
American  type  of  relapsing  fever  due  to  S.  Novyi,  and  an  Asiatic 
type  due  to  S.  Carteri. 

Eelapsing  Eever 

A  disease  characterised  by  the  occurrence  of  febrile  paroxysms 
associated  with  the  presence  of  spirochetes  (spirilla)  in  the  blood. 

Distribution. — The  disease  was  formerly  common  in  the  British 
Islands,  particularly  in  Ireland.  Its  association  with  destitution  gave 
it  the  name  "famine  fever."  Recent  epidemics  have  occurred  in 
Austria  and  Eussia.  In  epidemic  form  the  disease  is  most  common 
in  India,  particularly  the  Bombay  Presidency,  but  outbreaks  have 
occurred  in  recent  years  in  China,  Northern  Africa,  South  America, 
and  the  "West  Indies. 

Etiology. — The  disease  is  clue  to  the  presence  of  Spirochseta  Ober- 
meieri in  the  blood.     The  parasite  is  a  delicate  thread-like  organism, 

362 


DISEASES   DUE   TO   SPIROCHETES   IN   THE   BLOOD     363 

measuring  15  to  40  p  in  length,  0'25  p  in  breadth  at  its  widest  part. 
It  exhibits  a  number  of  spirals,  very  commonly  eight.  The  extent 
of  the  bending  varies  greatly.  The  organism  exhibits  extraordinary 
motility,  being  capable  of  progression  backwards  and  forwards  as  well 
as  of  performing  lateral  and  rotatory  movements. 

When  faintly  stained  with  a  Eomanowsky  method  the  spirilla 
appear  blue,  when  more  deeply  stained  they  are  red.  They  are  also 
stained  by  carbol-fuchsin  or  gentian  violet.  They  are  decolourised  by 
Gram's  method.  No  details  of  structure  can  be  detected  beyond  the 
existence  of  tapering  pointed  ends  and  slight  inequality  of  staining 
intensity,  the  central  portion  staining  least.  Attempts  to  cultivate  the 
spirilla  have  failed.  It  is  not  known  how  the  organisms  find  entrance 
to  the  body. 

Local  infectivity  is  very  marked,  but  the  disease  seldom  spreads 
widely.  Attendants  on  the  sick  are  especially  liable  to  attack,  and 
instances  of  successive  inhabitants  of  a  house  or  room  being  infected 
are  common. 

The  fact  that  other  spirilla  are  conveyed  by  ticks  has  led  to  inquiry 
in  this  direction.  The  spirillum  has  been  found  in  bugs,  and  is  known 
to  live  in  them  for  several  days.  Infection  has  been  conveyed  to 
monkeys  by  injecting  the  fluids  of  infected  bugs  crushed  immediately 
after  feeding,  but  bugs  crushed  forty-eight  hours  after  feeding  failed 
to  convey  infection. 

In  an  epidemic  in  India  Mackie  regarded  Pediculus  vestimentorum 
as  the  infecting  agent,  and  he  found  spirilla  in  the  secretion  expressed 
from  the  mouths  of  pediculi  from  infected  persons. 

The  blood  of  a  patient  in  the  apyrexial  period,  during  which  spirilla 
are  not  found,  is  still  infective  to  monkeys.  This  has  suggested  the 
existence  of  spores,  but  these  have  not  been  demonstrated  although 
"infective  granules"  have  been  described.  These  granules  may  be 
demonstrated  by  the  dark-ground  method  or  by  vital  staining.  Blood 
containing  spirilla  causes  relapsing  fever  when  injected  in  man, 
monkeys,  rats,  and  mice. 

Morbid  Anatomy. — The  general  picture  is  that  of  severe  septicaemia. 
There  are  subserous  haemorrhages,  and  enlargement  of  the  liver  and 
spleen,  and  catarrh  of  the  mucous  membranes.  The  splenic  capsule  is 
distended  and  smooth,  the  pulp  is  firm  and  the  Malpighian  bodies  are 
enlarged,  and  there  is  vascular  engorgement.  Spirilla  may  be  found 
free   and  in   polymorphonuclear   cells,   and   are  frequently  numerous. 


364    DISEASES   DUE   TO   SPIROCHETES   IN  THE  BLOOD 

The  liver  shows  cloudy  swelling.      Patches  of  catarrhal  or  fibrinous 
pneumonia  are  common. 

Symptoms. — The  incubation  period  varies  from  twelve  hours  to 
eight  days.  It  is  usually  two  to  five  days.  The  initial  symptoms  are 
malaise,  followed  by  chills  and  rigors.  There  is  headache,  pain  in  the 
back  and  limbs.  The  temperature  rises  to  104°  or  105°  F.,  the  pulse 
becomes  rapid.  Vomiting  sets  in,  and  haematemesis  and  jaundice  may 
occur.  The  patient  is  sleepless  and  wretched.  These  symptoms  persist 
till  the  third,  fifth,  or  more  usually  the  seventh  day,  when  they  suddenly 
terminate  by  crisis.  The  patient,  apart  from  some  exhaustion,  now 
feels  well,  but  after  seven  days  there  is  a  relapse,  followed  by  a  train 
of  symptoms  similar  to  the  first  but  often  of  shorter  duration.  The 
second  attack  usually  terminates  on  the  fifth  day,  and  is  generally 
followed  by  complete  recovery.  Occasionally  there  is  no  relapse  and 
on  the  other  hand  there  may  be  as  many  as  five.  There  is  very  profuse 
sweating  at  the  times  of  crisis.  The  common  complications  are  pneu- 
monia and  severe  diarrhoea.  Less  frequently  there  may  be  haemor- 
rhages, inflammation  of  lymphatic  glands,  eye  and  ear,  and  synovial 
membranes. 

The  Blood. — There  is  a  moderate  degree  of  anaemia  after  the 
paroxysm.  During  the  paroxysm  there  is  a  considerable  increase  of 
polymorphonuclear  leucocytes  and  lymphocytes,  and  spirilla  may  be 
found  in  the  peripheral  blood.  The  parasites  are  much  more  numerous 
after  the  second  day  of  the  paroxysm  than  at  the  beginning.  They  are 
for  the  most  part  free  and  actively  motile,  but  large  numbers  are  often 
seen  in  the  polymorphonuclear  leucocytes.  The  numbers  vary  very 
greatly  in  different  cases,  and  appear  to  be  very  unevenly  distributed 
in  the  blood.  Sometimes  they  are  abundant  enough  to  keep  the  whole 
microscopic  field  in  motion,  at  other  times  prolonged  search  may  fail 
to  reveal  them.  They  are  rarely  to  be  found  for  two  or  three  days  after 
a  paroxysm  is  over. 

Diagnosis. — In  the  early  stages  a  definite  diagnosis  may  be  impos- 
sible unless  the  parasite  is  found.  In  the  great  majority  of  cases  a  blood 
examination  will  make  the  diagnosis  clear. 

Lowenthal  has  shown  that  the  blood  during  the  afebrile  stage  will 
stop  the  movements  of  spirilla  in  blood  from  a  case  during  a  paroxysm 
when  they  are  incubated  together  for  half  an  hour. 


DISEASES   DUE   TO   SPIROCHETES   IN   THE   BLOOD     365 

Prognosis. — In  uncomplicated  cases  prognosis  is  good.  In  the 
British  epidemics  the  mortality  was  4  per  cent.,  but  it  seems  somewhat 
higher  in  India.  Death  occurs  usually  during  the  height  of  the  initial 
paroxysm,  and  is  generally  due  to  heart  failure.  A  few  cases  collapse 
after  the  crisis.  The  disease  is  more  unfavourable  at  the  extremes  of 
age.  Pregnant  women  abort  but  usually  recover.  Pneumonia  and 
severe  jaundice  are  generally  fatal,  and  a  few  cases  die  from  cerebral 
ruemorrhage. 

Treatment. — Prophylactic  treatment  consists  of  isolation  of  the 
sick  from  the  healthy,  and  great  care  must  be  exercised  to  avoid 
the  possibility  of  transmission  of  the  disease  by  vermin.  There  is  no 
specific  treatment  of  the  disease.  Quinine  is  useless.  Possibly  the 
serum  of  immunised  animals  might  do  good.  The  general  treatment 
must  be  along  lines  appropriate  for  the  management  of  any  severe 
febrile  affection.  During  the  apyrexial  period  the  patient  should  be 
fed  up  to  the  limits  of  his  digestive  powers  and  carefully  watched. 

Tick  Fever 

A  disease  characterised  by  febrile  paroxysms  resembling  those  of 
relapsing  fever,  associated  with  the  presence  of  Sjnrochcete  Duttoni  in 
the  blood  and  caused  by  the  bite  of  an  insect. 

Distribution. — The  disease  occurs  throughout  the  greater  part  of 
tropical  Africa,  in  Asia,  Egypt,  and  Algeria. 

Etiology. — The  disease  may  be  caused  by  the  bite  of  the  horse  tick, 
Omithoclorus  moubata,  and  by  the  Persian  poison  bug,  Argas  persicus. 
It  is  probable  that  infection  may  also  be  conveyed  by  lice  and  fleas. 
The  bite  gives  entrance  to  a  spirochete,  S.  Duttoni.  The  parasite  is 
identical  morphologically  with  S.  Obermeieri,  but  each  of  the  two 
forms  confers  immunity  against  itself  but  not  against  the  other. 
Inoculation  of  S.  Duttoni  into  monkeys  leads  to  a  much  more  severe 
disease  than  S.  Obermeieri.  S.  Duttoni  can  be  cultivated  outside  the 
body  in  special  media,  such  as  broth  containing  mouse  blood  and  yolk 
of  egg. 

Ticks  may  transmit  infection  from  animals  which  they  have  bitten 
during  the  afebrile  stage.  Leishman1  has  found  that  ticks  may  be 
1  Lancet,  1st  January  1910. 


366     DISEASES   DUE  TO   SPIROCHETES   IN  THE  BLOOD 

infective  although  no  spirochetes  can  be  found  in  their  tissues,  nor 
were  spirochetes  to  be  found  in  the  eggs  or  nymphs  although  the 
latter  gave  rise  to  infective  young  ticks.  Spirochetes  ingested  by 
ticks  disappear  by  the  tenth  day,  but  their  chromatin  core  breaks  up 
into  coccoid  granules,  which  may  be  found  free  in  the  gut  in  great 
numbers.  Inoculation  of  emulsions  of  these  granules  was  infective  to 
mice,  especially  if  the  tick  from  which  they  were  derived  had  been  kept 
for  a  day  or  two  at  34°  to  37°  C.  before  dissection.  Ticks  containing 
the  granules  develop  young  spirochsetes  when  kept  for  a  week  or  ten 
days  at  34°  C.  The  young  spirochete  probably  passes  into  the  wound 
made  by  the  tick-bite  from  the  secretion  of  its  Malpighian  tubes  or 
coxal  glands. 

Symptoms. — The  symptoms  are  identical  with  those  of  relapsing 
fever,  except  that  the  usual  duration  of  the  paroxysm  is  four  days  and 
relapses  are  more  frequent. 


CHAPTER  XLII 

FILARIASIS 

A  considerable  number  of  filarial  are  parasitic  in  man  but  only  a 
few  are  pathogenic.  The  embryos  of  F.  Bancrofti,  F.  loci,  F.  perstans,  and 
F.  demarquayi  are  found  in  the  blood.  Filaria  medinensis,  the  guinea- 
worm,  causes  dracontiasis.  Filaria  volvulus  is  found  in  lymphatic 
vessels  and  gives  rise  to  cystic  tumours. 


Filariasis  Due  to  Filaria  Bancrofti  (Filaria  Sanguinis 
Hominis  or  Filaria  Nocturna) 

Filaria  Bancrofti  causes  disease  of  lymphatic  vessels  and  glands, 
chylous  extravasations,  orchitis,  and  elephantiasis. 

Distribution.  —  Filariasis  is  widely  distributed  throughout  Asia, 
Australasia,  America,  and  Africa.  In  Europe  it  is  said  to  exist  near 
Barcelona  and  in  Turkey.  The  endemic  areas  are  curiously  circum- 
scribed for  some  reason  not  yet  understood. 

Etiology. — The  condition  is  caused  by  the  introduction  into  the 
body  of  filaria  by  means  of  a  mosquito  bite.  Many  different  species  of 
mosquito  are  capable  of  carrying  the  disease.  Culex  fatigans  is  the 
common  infecting  agent  in  the  West  Indies,  Myzomia  Bossii  in  India, 
Panoplites  Africanus  in  Central  Africa,  and  Fyretopliorus  costalis  and 
Stegomyia  fasciata  in  Nigeria. 

The  filaria  develops  in  the  thoracic  muscles  of  the  mosquito  and 
passes  to  the  labium.  When  the  mosquito  bites,  the  filaria  works  its 
way  though  Dutton's  membrane  on  to  the  skin.  There  it  may  find 
its  own  way  through  the  skin  or  it  may  pass  through  the  puncture 
made  by  the  mosquito.  No  more  is  known  of  the  filaria  till  its  adult 
condition  is  reached.  Adult  males  and  females  are  found  lying  together 
in  lymphatic  vessels.  Females  usually  preponderate.  The  females 
produce  the  embryos  or  microfilariae,  which  pass  through  the  thoracic 

3G7 


368  FILARIASIS 

duct  into  the  blood-stream.  When  these  microfilariae  are  ingested  by 
the  mosquito  they  escape  from  their  enclosing  membrane,  enter  the 
thoracic  muscles,  and  complete  their  cycle  of  development. 

Morphology  of  the  Parasites. — The  adult  worms  are  whitish  in  colour, 
long  and  filiform,  with  a  smooth  cuticle,  a  spherical  head  terminating  in 
a  simple  round  mouth.  The  tail  is  rounded.  The  male  is  smaller  than 
the  female,  and  measures  38"6  x  0'12  mm.     The  tail  is  curved. 

The  female  is  longer,  thicker,  and  rather  more  transparent  than  the 
male,  and  measures  76  to  100  x  0*185  mm.  Two|uterine  tubes  open 
from  a  single  vagina  and  run  nearly  the  whole  length  of  the  body. 
They  contain  eggs  in  all  stages  of  development.  The  younger  eggs  are 
oval,  measuring  50  x  34  p.  They  contain  a  coiled  embryo.  The 
embryo  enlarges  and  causes  the  egg-shell  to  elongate.  Finally,  they 
escape  through  the  genital  pore  and  enter  the  lymph  stream  and 
through  the  lymphatic  vessels  reach  the  blood.  The  microfilarise 
measure  from  280  to  320  /x  x  7'5  to  8'5  /*  (Low).  They  are  long, 
slender,  cylindrical  bodies,  with  a  rounded  anterior  and  a  tapering 
posterior  end.  They  are  enclosed  in  a  sheath  which  is  not  closely 
applied  at  the  ends  so  that  the  filaria  can  move  backwards  and  for- 
wards within  it.  The  anterior  extremity  possesses  a  proboscis  carrying 
a  minute  apical  spine  capable  of  being  covered  by  a  six-lipped  hood. 
Behind  the  extremity  the  body  is  covered  by  a  transversely  striated 
wall.  Inside  are  closely  packed  cells  whose  nuclei  are  readily  stained. 
In  unstained  specimens  the  central  mass  appears  granular  for  the  most 
part,  but  this  granular  aspect  is  interrupted  by  several  "  clear  spots." 
There  is  a  "  break  "  in  the  cell  column  50  p  from  the  head,  a  V-shaped 
irregular  spot  (Manson)  90  p  from  the  head,  and  a  "  tail  spot "  near  the 
caudal  extremity. 

Pathology. — If  the  parent  worms  lie  in  positions  in  which  they  do 
not  obstruct  the  flow  of  lymph,  and  if  they  are  not  accidentally  injured, 
no  symptoms  may  arise.  Symptoms  may,  however,  arise  in  two  ways. 
Either  the  parent  worms  may  mechanically  obstruct  an  important 
lymphatic  trunk,  or  the  female  worm,  as  the  result  of  some  injury,  may 
abort  and  produce,  instead  of  the  elongated  embryos,  the  comparatively 
broader  oval  eggs  which  may  block  up  small  lymph  channels. 

Sometimes  coiled-up  masses  of  worms  may  block  up  a  lymphatic 
trunk.  Considerable  irritation  and  inflammatory  proliferation  may  be 
set  up,  so  that  lymphatics  may  remain  blocked  after  the  worms  have 
died  and  disappeared.     The  engorgement  of  the  tissues  lowers  their 


EILAPJASIS  369 

trophic   power,  so   that  inflammation  and  even  abscess  formation  are 
not  uncommon. 

An  interesting  theory  is  that  smooth-skinned  elephantiasis  (E.  glabra) 
is  due  to  blocking  of  the  channels  in  the  lymphatic  glands,  while  rough 
elephantiasis  (E.  verrucosa),  in  which  the  skin  is  coarse  and  nodular,  is 
due  to  blocking  of  small  skin  capillaries. 

Symptoms. — Symptoms  vary  very  greatly  according  to  the  part 
involved.  Lymphangitis  with  cellulitis  and  erythema  associated  with 
fever  is  common.  Lymphadenitis,  usually  inguinal,  in  which  the  glands 
are  enlarged,  soft,  elastic  and  tender,  often  occurs.  In  some  cases  the 
glands  may  reach  an  enormous  size.  Microfilariae  may  be  obtained 
by  aspiration  with  a  hypodermic  syringe.  Lymphangiectasis  is  common 
and  usually  affects  the  scrotum  (lymph-scrotum).  The  condition  begins 
with  fever  and  local  inflammation.  The  part  becomes  swollen  and  elastic, 
and  the  skin  shows  clear  vesicles  containing  lymph  or  chyle  and  showing 
embryos.     Orchitis  and  hydrocele  frequently  occur. 

Chylous  Extravasations. — As  the  result  of  dilatation  and  rupture  of 
lymphatic  vessels  extravasations  of  chyle  may  occur.  A  frequent  seat 
of  extravasation  is  the  urinary  passages,  and  chyluria  or  haemochyluria 
results.  Chylous  diarrhoea,  chylocele,  and  chylous  ascites  are  more 
rare. 

Elephantiasis. — As  a  sequel  to  repeated  attacks  of  lymphangitis  the 
affected  part  fails  to  return  to  its  normal  size,  and  in  time  may  become 
greatly  enlarged.  The  condition  then  becomes  known  as  elephantiasis. 
The  skin  surface  may  be  smooth  or  rough.  The  lower  limb  and  the 
scrotum  are  the  usual  sites  of  the  condition.  Much  more  rare  s 
elephantiasis  of  the  vulva,  breast,  arm,  or  scalp.  Pendulous  cir- 
cumscribed masses  due  to  filarial  disease  have  been  noted  in  many 
situations. 

Blood  Changes. — The  red  cells  show  no  changes  unless  there  is 
haemochyluria  or  severe  diarrhoea  which  may  lead  to  anaemia.  A 
fair  rise  in  the  number  of  white  cells  may  occur.  Polymorphs, 
lymphocytes,  and  eosinophils  are  all  increased  in  recent  cases.  The 
lymphocytes  are  most  increased,  so  that  the  polymorph  percentage 
seldom  exceeds  70  per  cent.  Eosinophils  vary  from  4  to  10  per 
cent,  as  a  rule,  but  as  many  as  70  per  cent,  have  been  recorded. 
Their  numbers  appear  to  correspond  with  the  number  of  embryos  in 
the  circulating   blood,  and   as   these   are   usually   most   numerous   at 

24 


276 

10.20  p.m.   . 

808 

283 

11.10  p.m.   . 

.   1500 

476 

11.20  p.m.   . 

.   1224 

742 

370  FILAKIASIS 

night,  eosinophils  are  then  in  greatest  abundance.  Gulland 1  made 
the  following  observations  on  the  number  of  eosinophils  per  cubic 
millimetre  in  one  case : — 

11.10  a.m.      . 

3  p.m.      . 

4  P.M. 

10.10  p.m.      . 

The  microfilariee  occur  in  the  peripheral  blood,  but  are  only  found 
at  night.  They  begin  to  appear  between  5  and  7  p.m.  and  increase  till 
midnight.  Only  an  occasional  parasite  is  found  after  7  or  8  a.m. 
They  show  wriggling  and  twisting  movements  and  knock  about  the 
red  cells,  but  they  have  no  power  of  locomotion.  Their  numbers  vary 
greatly.  Manson  states  that  as  many  as  500  may  occur  in  a  single 
film,  but  in  most  of  the  cases  we  have  seen  in  this  country,  and  in  films 
sent  us  from  abroad,  the  number  is  small. 

In  the  daytime  the  microfilarise  live  in  the  lungs  and  large  thoracic 
vessels.  The  explanation  of  their  periodicity  in  the  peripheral  circula- 
tion is  not  known,  but  obviously  their  presence  there  at  night  adapts 
them  to  the  habits  of  the  mosquito.  The  filaria  of  the  South  Sea  Islands, 
which  is  identical  with  F.  nocturna,  shows  no  periodicity. 

Treatment. — Treatment  is  purely  symptomatic. 

Filariasis  Due  to  Filaria  Loa 

Filaria  loa  is  a  parasite  of  superficial  fibrous  tissue.  Its  chief 
endemic  centre  is  the  West  Coast  of  Africa.  The  male  is  a  slender 
transparent  worm  tapering  to  each  extremity  and  measuring  25  to 
34x0-27  to  0-45  mm.  The  female  measures  44  to  63x0-38  to  0*5 
mm.  The  microfilaria  (known  as  Filaria  diurna)  measures  210  to  280 
x  7  to  7'5  /*.  These  embryos  pass  into  the  circulation  by  day  and 
are  not  found  at  night,  and  their  appearance  in  the  peripheral  blood 
is  not  altered  by  changing  the  habits  of  their  host  in  regard  to  sleep. 
Their  number  is  always  scanty. 

The  embryos  do  not  cause  disease. 

The  adult  filaria  may  cause  slight  local  disturbance  in  the  course  of 

its  wanderings  in  the  connective  tissues,  and  may  give  rise  to  movements 

visible  on  the  surface.     The  symptoms  are  of  more  importance  when 

a  filaria  finds  its  way  into  the  conjunctiva  or  anterior  chamber  of  the 

1  Brit.  Med.  Journ.,  5th  April  1902. 


FILAEIASIS  371 

eye.  In  these  situations  it  may  cause  irritation  and  interference  with 
vision.  The  evanescent  tumours  known  as  Calabar  swellings  are 
probably  due  to  the  presence  of  F.  loa  in  the  tissues.  They  are 
associated  with  marked  eosinophilia. 

Treatment. — When  a  filaria  is  localised  by  its  movements  or  is  seen 
in  the  eye  it  may  be  removed  through  an  incision.  Calabar  swellings 
are  best  treated  by  local  sedative  applications. 

Filariasis  Due  to  Filaria  Persians 

The  adult  worms  usually  lie  free  in  the  connective  tissue  of  the 
abdomen.  Microfilariae  pass  from  the  uterus  of  the  adult  into  the 
circulating  blood.  As  the  microfilariae  escape  from  their  membrane 
they  have  active  powers  of  locomotion.  They  measure  200  to  230  /^  x 
4*5  to  5  ,«-.     A  shorter  type  has  been  noticed. 

There  is  no  periodicity  in  their  appearance  in  the  peripheral  blood. 
They  are  never  numerous,  and  are  not  pathogenic. 

Filariasis  Due  to  Filaria  Demarquayi 

This  parasite  is  found  in  certain  West  Indian  Islands  and  elsewhere. 
The  microfilariae  resemble  the  preceding  variety  except  in  the  more 
pointed  shape  of  the  caudal  extremity,  which  extends  beyond  the 
column  of  nuclei.  They  show  no  periodicity.  The  parent  worms 
inhabit  loose  fibrous  tissue  and  appear  to  be  non-pathogenic. 

Literature 

See  Brit.  Med.  Journ.,  15th  November  1913. 


CHAPTEE  XLIII 

PIKOPLASMATA— HiEMOGREGAEINIDA— HALTEEIDIUM— 

ANAPLASMATA 

PlROPLASMATA 

These  parasites  belong  to  the  hsemosporidia.  They  are  ovoid  or  pear- 
shaped,  with  one  or  two  chromatin  bodies.  They  are  found  in  the  red 
blood  corpuscles.  They  multiply  by  dividing  into  two  or  more  spores. 
Actively  motile  spores  may  be  seen  in  the  plasma.  Piroplasmata  do 
not  produce  pigment.  They  have  not  been  definitely  demonstrated 
in  man,  but  affect  horses,  cattle,  sheep,  dogs,  rats,  fowls,  etc.  There 
are  several  different  species,  many  of  which  cause  pyrexia  or  hsemo- 
globinuria  or  both  in  animals.  They  are  transmitted  by  ticks,  which 
remain  infective  through  several  generations. 

Literature 

Fantham,  Quart.  Journ.  Micros.  Science,  1906,  1907.  Nuttall  and  Graham 
Smith,  Journ.  of  Hygiene,  1906,  1907  (P.  canis).  Castellani  and  Chalmers,, 
Manual  of  Tropical  Medicine,  1910. 

PLemogregarinida 

Young  forms  are  found  in  the  red  corpuscles  of  reptiles,  amphibians, 
birds,  and  in  a  few  mammals ;  older  forms  are  found  in  the  plasma. 
Sporulation  occurs  in  the  cells  of  liver,  bone-marrow,  and  other  organs. 
The  chromatin  is   scattered  throughout  the  nucleus. 

Only  part  of  the  protoplasm  divides  into  spores,  which  may 
accumulate  in  the  distended  parent  cell.  The  parasites  do  not  produce 
pigment. 

Leucocytozoa  are  found  in  the  dog,  cat,  rat,  and  palm  squirrel. 

Leucocytozoon  canis  is  transmitted  by  ticks. 

Literature 

Castellani  and  Chalmers,  Manual  of  Tropical  Medicine,  1 9 1 0,  p.  3 1 9.  Doflein, 
Lehrbuch  der  Protozoenhmde,  1909,  679.       Porter,  Science  Progress,  hi.  1910 

372 


HALTERIDIUM  373 

(Leucocytozoa).  Wenyon,  Parasitology,  hi.  1910  (Leucocytozoa).  Henry, 
Journ.  of  Path,  and  Bad.,  xiv.  1910  (Hsemoprotozoa  of  British  Sea  Fish). 
Welsh  and  others,  Journ.  of  Path,  and  Bad.,  xiv.  1910  (Hsemogregarinida  of 
Australian  Fauna).  See  also  various  abstracts,  Folia  Hcematologica,  iv. 
supplement,  1907. 

Halteridium   Danilewskyi 

These  parasites  are  found  in  the  red  corpuscles  of  birds.  Schaudinn, 
in  1904,  concluded  that  they  were  stages  in  the  life-history  of  trypano- 
somes.  A  certain  amount  of  support  has  been  given  by  others  to  this 
view,  but  on  the  other  hand  most  observers  consider  that  Schaudinn  was 
misled  by  a  double  infection  of  a  halteridium  and  a  trypanosome. 

Literature 

A  good  account  of  morphology  is  given  by  Welsh,  Journ.  of  Path,  and 
Bad.  1911. 

Anaplasmata 

A  minute  protozoal  parasite,  the  anaplasma  marginale,  has  been 
shown  by  Theiler  to  be  the  cause  of  the  disease  known  as  gall  sickness 
which  affects  cattle  in  South  Africa.  Similar  bodies  affect  cattle  in 
North  and  South  America.  Anaplasmata  were  at  one  time  thought 
to  be  a  phase  in  the  life-cycle  of  piroplasma  bigeminum,  but  they  appear 
to  be  distinct,  although  there  is  a  close  association  between  the  two. 
Thus  an  animal  inoculated  with  piroplasmata  invariably  develops 
anaplasmosis  from  twenty  to  thirty  days  after  the  red  water  reaction. 
A  special  variety,  anaplasma  centrale,  has  been  discovered  by  Theiler, 
and  its  virulence  seems  to  be  less  than  that  of  the  marginal  parasite. 

Anaplasmosis  is  transmitted  by  ticks.  In  South  Africa,  the  blue 
tick,  Boophilus  decoloratus,  is  the  carrier. 

Anaplasmata  are  spherical  bodies  which  seem  to  consist  entirely  of 
chromatin.  They  vary  in  size  from  a  minute  point  to  about  1  p.  Some 
of  the  bodies  are  marginal;  some  are  central,  but  the  majority  are 
found  a  short  distance  from  the  edge  of  the  red  corpuscle. 

Considerable  discussion  has  arisen  in  connection  with  the  discovery 
of  similar  bodies  in  the  blood  of  a  large  number  of  domestic  and  wild 
animals.  The  question  which  arises  is  whether  spherical  intracorpuscular 
bodies  staining  like  chromatin  are  to  be  regarded  as  anaplasmata 
or  Jolly  bodies.  A  large  number  of  observations  on  different  animals 
has  been  made  by  Dodd.  He  found  very  numerous  chromatin  bodies, 
varying  in  size  from  1  to  4  /*,  in  marsupials,  and  considers  that  these 


374  ANAPLASMATA 

are  normal  appearances,  although  under  certain  conditions  they  may 
be  present  in  abnormal  numbers. 

It  may  be  concluded  that  between  the  pathogenic  anaplasmata  of 
cattle  on  the  one  hand,  and  the  normal  Jolly  bodies  of  marsupials  on 
the  other,  there  is  a  group  of  chromatin  bodies  found  in  the  red 
corpuscles  of  a  large  number  of  other  animals  whose  nature  must  in 
the  meantime  be  left  an  open  question. 

Literature 
Dodd,  Journ.  of  Compar.  Path,  and  Therapeutics,  xxvi.  1913,  p.  97. 


APPENDIX   A 

SPLENECTOMY  IN  PERNICIOUS  ANAEMIA 

While  proofs  of  Chapter  XIV.  were  in  the  press  the  question  of  treating 
pernicious  anaemia  by  splenectomy  began  to  assume  some  importance,  and 
a  number  of  cases  in  which  improvement  has  followed  the  operation  are  now 
on  record.  Eppinger  reports  two  cases  in  which  there  was  an  immediate 
rise  in  the  number  of  red  corpuscles  which  reached  normal,  an  increase  of 
body  weight,  and  a  disappearance  of  subjective  symptoms. 

V.  Decastello  records  the  case  of  a  woman,  aged  52,  with  typical  symp- 
toms and  blood  picture  (red  corpuscles,  1,236,000).  Under  treatment  by 
the  ordinary  therapeutic  measures  the  red  cells  fell  to  750,000,  Hb.  17  per 
cent.  There  was  oedema,  ascites,  and  drowsiness,  and  death  seemed  immi- 
nent. Splenectomy  was  performed.  In  ten  days  the  oedema  and  icterus 
had  disappeared.  The  blood  showed  a  large  invasion  of  normoblasts,  and  in 
eleven  weeks  the  count  had  risen  to  4,032,000  with  Hb.  83  per  cent. 

Klemperer  and  Hirschfeld  report  three  cases.  One,  a  woman  aged  63, 
died  of  bronchopneumonia.  Both  the  others  improved.  In  one  the  cor- 
puscles rose  from  950,000  to  1,730,000;  in  the  other  from  1,100,000  to 
2,680,000.  In  all  three  there  was  an  enormous  normoblast  reaction  and  a 
great  number  of  corpuscles  showing  Jolly  bodies. 

Klemperer  subsequently  records  ten  cases.  Two  died  immediately  after- 
operation.  In  eight  there  was  improvement  in  health  which  was  reflected  in 
the  blood,  but  in  only  one  case  did  the  blood  picture  of  pernicious  anaemia 
disappear. 

Huber  had  a  case  in  a  woman,  aged  34.  She  was  at  first  too  weak  for 
operation,  and  was  treated  with  intramuscular  injections  of  defibrinated  blood. 
There  was  temporary  improvement,  followed  by  a  high  temperature  and  the 
appearance  of  petechiae.  As  a  last  resource  the  spleen  was  excised.  She 
stood  operation  well,  and  rapidly  improved.  After  five  weeks  erythrocytes 
numbered  2,500,000,  Hb.  50  per  cent.  Three  months  afterwards  the  patient 
could  walk,  but  prognosis  was  apparently  not  good.  At  a  discussion  in  the 
Berlin  Gesellschaft  fiir  Chirurgie,  W.  Turk  stated  that  if  in  pernicious 
anaemia  the  spleen  had  an  injurious  action  it  was  different  from  that  in 
haemolysis  and  some  other  agent  had  to  be  assumed.  Splenectomy,  however, 
played  a  part.  Patients  recovered  at  first,  but  the  state  of  the  blood  never 
became  normal  again.  Miihsam  referred  to  eleven  cases.  One  died  from 
purulent  bronchitis,  two  from  a  hemorrhagic  diathesis,  one  from  myelitis  ;  in 
a  fifth  the  blood  went  from  bad  to  worse.  Six  cases  were  alive,  and  had 
regained  some  strength,  but  were  not  in  good  health.  It  is  unnecessary  to 
refer  to  further  cases. 

375 


376  APPENDIX 

The  argument  for  the  operation  is  based  upon  the  good  results  obtained 
by  splenectomy  in  Banti's  disease,  the  suggestion  that  in  pernicious  anaemia 
there  is  a  pathological  exaltation  of  the  normal  function  of  the  spleen  in 
dealing  with  old  and  effete  blood  corpuscles,  and  a  theory  that  the  spleen 
produces  a  hormone  which  inhibits  the  action  of  the  bone-marrow. 

The  first  argument  seems  to  us  irrelevant,  as  there  is  no  likeness  between 
Banti's  disease  and  pernicious  anaemia.  As  regards  the  second,  there  is  no 
doubt  that  the  spleen  takes  up  old  and  damaged  red  corpuscles,  and  that 
this  function  may  be  increased  by  the  larger  number  of  abnormal  corpuscles 
brought  to  it  in  pernicious  anaemia  as  suggested  on  page  123.  In  our 
researches  on  blood  destruction  in  normal  and  spleenless  dogs  we  found  that 
damaged  corpuscles  were  removed  from  the  circulation  more  rapidly  in 
animals  with  the  spleen  intact.  Whether  a  case  of  pernicious  anaemia  is  to 
be  much  benefited  by  the  continued  presence  in  the  circulation  of  corpuscles 
which  the  spleen  should  have  dealt  with  is  open  to  question.  The  effect  on 
the  corpuscles  is  probably  rather  a  delay  of  their  funeral  than  an  extension 
of  their  usefulness. 

As  regards  the  suggested  inhibitory  effect  of  the  spleen  on  the  bone- 
marrow  we  may  say  that  there  is  no  evidence  in  its  favour,  and  in  our 
splenectomy  experiments  the  evidence  was  against  it. 

A  point  to  be  kept  in  view  is  that  in  some  instances  we  have  met  with 
appearances  of  supplementary  blood  formation  in  the  spleen  in  cases  of 
pernicious  anaemia. 

A  feature  which  makes  judgment  specially  difficult  is  the  capricious 
course  of  the  disease,  which  we  have  already  pointed  out. 

We  have  never  had  splenectomy  performed,  and  only  once  recommended 
it.  The  case  was  that  of  a  woman  of  55  who  eight  months  before  had 
recovered  in  our  wards  under  arsenic  from  a  severe  first  attack  of  pernicious 
anaemia.  She  was  brought  in  a  second  time  in  a  very  feeble  condition,  with 
the  usual  lemon-yellow  pallor,  fever,  gastro-intestinal  symptoms,  and  a  rapid, 
feeble  heart.  The  red  count  was  670,000,  haemoglobin  16  per  cent.  After 
five  days,  on  small  closes  of  arsenic,  the  reds  rose  to  780,000,  haemoglobin  20 
per. cent.  A  week  later  the  count  had  fallen  again  to  650,000,  haemoglobin 
16  per  cent.,  and  the  general  symptoms  had  only  slightly  improved.  We 
proposed  splenectomy  as  a  last  resort,  as  there  seemed  no  chance  of  her 
recovery  under  ordinary  measures,  but  the  patient  and  her  friends  were  most 
unwilling  to  allow  operation.  Some  time  was  taken  up  by  negotiations,  and 
the  blood  was  not  examined,  as  it  was  intended  to  do  it  just  before  she  went 
to  the  surgical  side.  She  began  to  improve  quite  suddenly,  and  the  next 
examination  of  the  blood  a  fortnight  after  the  last  one  showed  reds  2,070,000, 
haemoglobin  45  per  cent.,  with  great  general  improvement.  Both  blood  and 
patient  have  steadily  got  better  under  arsenic  by  the  mouth — of  course  along 
with  the  other  usual  measures — and  the  reels  are  now  just  under  4,000,000, 
haemoglobin  82  per  cent.  Had  the  spleen  been  removed  when  we  first  pro- 
posed it  the  sudden  improvement  would  certainly  have  been  ascribed  to  the 
operation. 

This  case  well  illustrates  the  danger  of  drawing  conclusions  from  too 


APPENDIX  377 

narrow  a  basis,  especially  in  a  disease  so  uncertain  in  its  prognosis  as  pernicious 
anaemia.  The  more  recent  statistics  bring  out  both  the  dangers  and  the 
ultimate  failure  of  the  procedure  to  produce  complete  cure.  Patient  treat- 
ment along  the  ordinary  lines  would  probably  have  produced  results  at  least 
as  good  as  those  in  Miihsam's  series,  and  possibly  better,  certainly  without  so 
large  a  percentage  of  immediately  fatal  cases. 

We  conclude  that  as  the  seat  of  the  disease  is  the  bone-marrow  and  not 
the  spleen,  a  cure  is  not  to  be  looked  for  from  splenectomy.  The  utmost 
benefit  that  can  be  expected  from  the  operation  is  a  stimulus  to  the  marrow 
from  haemorrhage,  and  a  moderate  lengthening  of  the  sojourn  in  the  circulating 
blood  of  certain  red  corpuscles  of  doubtful  value  to  their  host. 

We  are  unable  to  say  that  such  benefit  is  ever  likely  to  be  worth  the  risk 
involved  in  obtaining  it. 

Literature 

Eppinger,  MilncJi.  med.  Woch.,  1913,  p.  1236;  Berlin.  Jclin.  Woch.,  1913. 
V.  Decastello,  Wein.  Jclin.  Wocli.,  1913,  p.  951.  Klemperer  and  Hirschfeld, 
TJierapie  d.  Gegenwart,  1913.  Klemperer,  ibid.,  1914,  p.  1.  Huber,  Berlin. 
Jclin.  Woch.,  1913.  Turk,  Dent.  med.  WocJi.,  1914,  p.  371.  Miihsam,  Deut.  med. 
Woch.,  1914,  p.  377.  Ranzi,  MiincJi.  med.  Woch.,  1913,  p.  2819.  Barbier, 
Bull,  de  la  Soc.  de  Mid.  de  Paris,  1913,  p.  355.  Harpole  and  Fox,  Surg.  Gynec. 
and  Obstet.,  1914. 


APPENDIX   B 

A  NEW  STAINING  METHOD 


In  examining  films  of  myelocythsemia,  one  finds  that  none  of  the  single  stains 
in  ordinary  use  are  sufficient  to  give  a  complete  picture.  Ehrlich's  triple 
stain  gives  the  best  picture  of  myelocytes,  but  has  the  disadvantage  that 
lymphocytes  are  very  poorly  stained,  and  the  basophil  series  not  at  all.  On 
the  other  hand,  it  is  very  difficult,  in  films  stained  with  Jenner,  to  distinguish 
with  certainty  between  some  of  the  myelocytes  and  the  cells  of  the  lympho- 
cyte series.  With  Leishman  and  other  Romanowsky  stains,  the  difficulty  is 
even  greater,  and  one  finds  the  differential  counts  made  with  Ehrlich  on  the 
one  hand,  and  a  Romanowsky  stain  on  the  other,  from  the  same  blood,  show 
wide  differences  even  in  the  hands  of  skilled  observers.  We  find  that  this 
difficulty  can  be  got  over  by  combination  of  the  triple  stain  and  Jenner. 
The  films  are  fixed  with  heat,  and  we  prefer  to  use  Cabot's  method  of  doing 
so,  bringing  the  films  to  140°  C.  in  an  oven  with  fair  rapidity,  and  then 
allowing  them  to  cool  rapidly.  Stain  with  triple  stain  for  three  to  five 
minutes  or  longer,  wash  quickly  in  distilled  water,  then  in  Jenner,  without 


378  APPENDIX 

previous  drying,  for  a  minute  or  such  time  as  may  be  desirable  from  the 
known  strength  of  the  solution.  Wash  again  in  distilled  water  and  allow  to 
dry.  Mount  in  balsam.  The  Jenner  reinforces  the  nuclear  stain  throughout, 
though,  as  is  always  the  case  with  heated  films,  nuclear  structure  is  not  so 
well  preserved  as  with  the  methyl-alcohol  fixing  alone.  The  myelocytes, 
polymorphs,  and  eosinophils  retain  the  triple  character  of  staining,  as  do  also 
the  red  cells,  but  in  addition,  the  basophil  granules  are  well  brought  out,  and 
in  particular  those  of  the  basophil  myelocytes,  which  with  Jenner  alone  are 
apt  not  to  be  preserved,  but  which  are  evidently  fixed  by  the  heat.  Some  of 
the  basophils,  as  Kanthack  and  Hardy  pointed  out  long  ago,  are  explosive, 
and  their  granules  are  found  scattered  round  the  nucleus.  The  cells  of  the 
lymphocyte  series  show  the  characteristic  blue  staining  of  the  cell  body,  and 
generally  one  attains  an  amount  of  detail  in  this  way  which  we  have  not 
seen  by  any  other  method.  Leishman  does  not  make  so  satisfactory  a  com- 
bination. The  characteristic  red  stain  of  the  chromatin  is  not  brought  out, 
and  it  acts  like  a  rather  diffuse  Jenner  stain.  If  by  any  chance  films 
have  been  overheated,  the  staining  can  still  be  carried  out  by  warming 
the  film  while  it  is  being  stained  with  Ehrlich,  and  by  adding  a  few 
drops  of  water  to  the  Jenner  stain  in  its  turn,  and  heating  that  also. 
One  can,  indeed,  get  very  satisfactory  preparations  in  this  way,  as  the 
overheating  fixes  the  granules  exceedingly  well. 


INDEX 


Abscess,  293 

cerebral,  322 

hepatic,  307 

pulmonary,  314 
Acetanilide,  299 
Acholuric  jaundice,  269 
Acromegaly,  310 
Actinomycosis,  289 
Acute  post-haemorrhagic  ansemia,  169 
Acute  rheumatism,  323 
Acute  yellow  atrophy  of  liver,  307 
Addis'  method  of  estimating  coagulation 

time,  40 
Addison's  disease,  310 
Adenoids,  313 
iEstivo-autumnal  fever,  334 
Alt'anassiew's  solution,  17 
African  tick  fever,  365 
Ague,  325 
Alcohol,  301 
Alcohol  and  ether,  29 
Alkalinity  of  the  blood,  41 
Altitudes,  effect  of,  61 
Anaemia  pseudoleukaemica  infantum,  266 
Anaemias  of  infancy,  265 
Anaesthesia  arid  lymphatism,  275 
Anaesthetics,  302 
Anaplasmata,  373 
Aniline,  299 

Animal  parasites,  79,  305 
Animals,  blood  of,  88 
Anisocytosis,  54 
Ankylostoma  duodenale,  305 
Anopheles,  325 
Anthrax,  285 
Antithrombin,  244 
Aplastic  anaemia,  175 
Appendicitis,  292 

Arneth's  classification  of  leucocytes,  76 
Arsenic,  301 

Arthritis,  rheumatoid,  323 
Ascaris  lumbricoides,  305 
Ascites,  308 
Aseptic  wounds,  298 
Asthma,  313 
Azur  granules,  66,  69 

Bacteriological  examination,  47 
Banti's  disease,  179 
Barlow's  disease,  260 
Basophil  leucocytes,  66 


Basophil  myelocytes,  68 

Basophilia,  punctate,  of  red  corpuscles,  56 

Beckmann's  cryoscope,  45 

Bence  Jones'  protein,  203,  238 

Beri-beri,  285 

Bilharziosis",  320 

Bilious  remittent  fever,  235 

Blackwater  fever,  346 

Blastomycosis,  289 

Blair  Bell's  calcium  method,  53 

Blood-plates,  82 

enumeration  of,  17 

Boils,  293 

Bone-marrow,  95 

Boycott  and  Chisolm's  method  of   esti- 
mating alkalinity,  42 

Bright's  disease,  319 

Bronchiectasis,  314 

Bronchitis,  313 

Bronzed  diabetes,  191 

Bubonic  plague,  285 

Buckmaster's  method  of  estimating  co- 
agulation time,  40 

Biirker's  haemocytometer,  9,  10 

Calabar  swellings,  371 
Calcium  content  of  blood,  53 
Cancer,  298 
Capsule  corpuscle,  58 
Carbon  monoxide  method,  47 
Carbuncle,  293 
Care  of  instruments,  25 
Catarrhal  jaundice,  306 
Cerebral  abscess,  322 
Cerebral  haemorrhage,  322 
Cerebral  tumour,  322 
Cerebro-spinal  meningitis,  284 
Cestodes,  306 
Chemical  fixation,  29 
Childhood,  85 
Chloral  hydrate,  301 
Chloroform,  302 
Chloroma,  222 
Chlorosis,  153 

blood  changes,  161 

complications,  162 

course,  162 

definition,  153 

diagnosis,  163 

etiology,  153 

iron  in,  166 


380 


INDEX 


Chlorosis — 

Lorrain  Smith's  theory,  156 

organic  iron  in,  166 

pathology,  154 

prognosis,  162 

prophylaxis,  164 

symptoms,  158 

treatment,  164 
Choice  of  staining  methods,  36 
Cholaernia,  306 
Cholaernia,  congenital,  269 
Cholera,  2S4 
Chorea,  321 

Chronic  bronchitis,  313 
Cirnex  lectularius,  350 
Cimex  rotundatus,  350 
Circulatory  system,  312 
Cirrhosis  of  liver,  307 
Classification  of  leucocytes,  65 
Cleaning  of  instruments,  25 
Coagulation  of  blood,  243 
Coagulation  time,  39 
Colchicum,  301 
Colitis,  304 
Colour  index,  24 
Colour  of  erythrocytes,  54 
Combined  fixing  and  staining  methods. 

32 
Congenital  anaemia  with  jaundice,  272 
Congenital  family  cholaernia,  269 
Congenital  heart  disease,  312 
Constipation,  304 
Counting  chambers,  4 
Cretinism,  310 
Cryoscopy,  44 
Cyanosis,  hematogenous,  186 

microbic,  190 
Cystitis,  320 

Dare's  haemoalkalmieter,  42 

Dare's  haernoglobinometer,  23 

Dark-ground  illumination,  48 

Deetjen's  method,  82 

Degenerations  of  marrow,  98 

Dengue,  285 

Denning  and  "Watson's  viscosimeter,  38 

Dermatitis  herpetiformis,  318 

Development  of  blood-cells,  100 

Development  of  red  cells,  111 

Diabete  Bronze,  191 

Diabetes  mellitus,  322 

Diarrhoea,  304 

Differential  counting  of  leucocytes,  69 

Digestion  leucocytosis,  74 

Diluting  fluids,  4,  14,  17 

Diphtheria,  281 

Distomiasis,  80 

Dohle's  inclusion  bodies,  279 

Dourine,  357 

Dracontiasis,  80 

Drouin's  method  of  estimating  alkalinity, 

41 
Drug  leucocytosis,  76 


Drugs,  299 
Ductless  glands,  309 
Duodenal  ulcer,  303 
Durham's  pipette,  11 
Dysentery,  284 

Eclampsia,  321 

Ectopic  gestation,  320 

Ehrlich's  triple  stain,  30 

Elephantiasis,  369 

Emphysema,  314 

Endocarditis,  312 

Enteric  fever,  281 

Enteritis,  304  •■ 

Enumeration  of  blood-plates,  17 

Enumeration  of  leucocytes,  14 

Enumeration  of  red  corpuscles,  3 

Eosine  and  methylene  blue,  30 

Eosinophil  leucocytes,  65 

Eosinophil  myelocytes,  68 

Eosinophilia,  79 

Epidemic  meningitis,  284 

Epilepsy,  321 

Erysipelas,  294 

Erythema,  318 

Erythremia,  186 

Eiythroblastoma,  237 

Erythroblasts,  62 

Erythrocytes,  54 

Estimation  of  haemoglobin,  18 

Ether,  302 

Ethyl  chloride,  302 

Exophthalmic  goitre,  310 

Family  cholaernia,  269 

Fatty  degeneration  of  leucocytes,  52 

Fatty  degeneration  of  marrow,  98 

Ferments,  leucocyte,  72 

Ferrometer,  24 

Fevers,  leucocytosis  in,  76 

Fibrin  network,  2 

Fibroid  degeneration  of  marrow,  98 

Filaria  Bancrofti,  367 

F.  demarquayi,  373 

F.  loa,  370 

F.  medinensis,  80,  367 

F.  perstans,  371 

F.  volvulus,  367 

Filariasis,  80,  367 

Filix  mas,  302 

Films,  spreading,  27 

Fixation  of  films,  29 

Fleischl-Miescher  hsemoglobinonieter,  21 

Fly  disease,  357 

Foetal  marrow,  95 

Formol-alcohol,  29 

Formol  vapour,  29 

Fractures,  298 

Fragility  of  red  corpuscles,  46 

Fresh  specimens,  2 

Functions  of  leucocytes,  70 

Gall-stones,  307 


INDEX 


381 


Gas  poisoning,  302 

Gastric  ulcer,  303 

Gastritis,  303 

Gaucher's  disease,  183 

Gelatinous  degeneration  of  marrow,  98 

Genealogy  of  blood-cells,  113 

General  diseases,  322 

General  paralysis,  322 

German  measles,  280 

Giemsa's  stain,  30 

Gierke's  method,  52 

Glanders,  285 

Glassy  body,  58 

Glycogen  reaction,  49 

Goitre,  exophthalmic,  310 

Gonorrhoea,  294 

Gout,  323 

Gowers'  hsemocytometer,  11 

Gowers'  hasmoglobinonieter,  18 

Gowers'  solution,  4 

Granular  polychromasia,  56 

Granules,  leucocyte,  69 

Guinea-worm  infection,  80 

H^ematin  and  eosine,  32 
Haematocrit,  13 
Hsematogenesis,  95,  111 
Haemtaogenous  cyanosis,  186 
Haemochromatosis,  191 
Haemoconia,  84 
Haemocytometers,  4 
Haemoglobin,  estimation,  19 
Haemoglobinometers,  19 
Hasmoglobinuria,  paroxysmal,  262 
Haemogregarinidae,  372 
Hemolytic  agents,  299 
Haemophilia,  240 
Haemorrhage,  169 
cerebral,  322 
Haldane  and  Lorrain  Smith's  method,  47 
Haldane's  haemoglobinometer,  19 
Hall's  haemoglobinometer,  24 
Halteridium,  373 
Hammerschlag's     method     for     specific 

gravity,  43 
Hayem's  solution,  4 
Heart  disease,  312 
Heat,  effect  on  corpuscles,  55 
Heidenhain's  iron-haematoxylin  method, 

32 
Heidenhain's  law,  103 
Hemeralopia,  259 
Henoch's  purpura,  255 
Hirschf eld's  pipette,  12 
Hodgkin's  disease,  226 
Howell's  bodies,  57 
Hyaline  leucocytes,  67 
Hydrophobia,  285 

Illuminating  gas  poisoning,  302 
Inclusion  bodies,  279 
Infancy,  85 
Infancy,  blood  diseases  in,  265 


Infancy,  leucocytes,  74 
Infancy,  red  corpuscles,  61 
Infantile  kala-azar,  354 
Infantile  scurvy,  260 
Infantile  splenic  anaemia,  266 
Infectious  disease,  278 
Infective  granules,  363,  366 
Inflammations,  290 
Influenza,  281 
Instruments,  care  of,  25 
Intestinal  parasites,  305 
Iodides,  300 
Iron-haematoxylin,  32 

Jaundice,  306 

acholuric,  269 

congenital  and  anaemia,  272 
Jenner's  stain,  32 
Jolly  bodies,  57 

Kahler's  disease,  237 
Kala-azar,  350 
Kala-azar,  infantile,  354 
Kurloft's  bodies,  90 

Lactation,  87 

Laked  blood,  55 

Large  mononuclear  leucocytes,  67 

Laverania  malariae,  329 

Lead,  300 

Leishman-Donovan  body,  350 

Leishman's  method,  34 

Leprosy,  289 

Leucanaemia,  225 

Leucocyte  granules,  69 

Leucocytes,  65 

Leucocytes,  antitoxin  formation,  74 

Leucocytes,  classification,  65 

Leucocytes,  enumeration,  14 

Leucocytes,  functions,  70 

Leucocytes,  general  characters,  65 

Leucocytes,  granules,  69 

Leucocytes,  numbers,  65 

Leucocythaemia,  193 

in  infancy,  265 
Leucocytosis,  73 
Leucocytozoa,  372 
Leucopenia,  73 
Leukaemia,  193 
Leukaemia,  mixed  forms,  221 
Lipaemia,  191 
Liver,  diseases  of,  306 
Lung,  abscess,  314 
Lupus,  318 
Lymphadenoma,  226 

abdominal,  228 

blood  changes,  230 

diagnosis,  233 

etiology,  226 

glandular  form,  228 

pathology,  226 

prognosis,  232 

symptoms,  227 


382 


INDEX 


Lymphadenoma — 

thoracic,  228 

treatment,  235 
Lymphatic  glands,  309 
Lymphatic  leukaemia,  195 

acute,  201 

blood  changes,  204 

chronic,  203 

diagnosis,  207 

etiology,  195 

hyperplastic,  201 

morbid  anatomy,  195 

pathology,  197,  199 

prognosis,  207 

symptoms,  201 

treatment,  208 
Lymphatism,  294 
Lymphocytes,  66 
Lymphocytoma,  237 
Lymphocytosis,  77 
Lymphosarcoma,  297 

Macrogametocyte,  326 
Malaria,  325 

sestivo-autumnal,  334 

algid,  335 

bilious  remittent,  335 

blood  changes,  337 

cerebro-spinal,  336 

chronic,  336 

cycle  of  Golgi,  292 

definition,  325 

diagnosis,  341 

diaphoretic,  335 

distribution,  325 

etiology,  325 

gastro-intestinal,  336 

hsemorrhagic,  335 

incubation  period,  326 

Laverania  malarise,  329 

parasites,  life-history,  325 

pathology,  330 

pernicious,  335 

Plasmodium  malarise,  328 

Plasmodium  vivax,  327 

prognosis,  342 

prophylaxis,  343 

quartan,  334 

quartan  parasite,  328 

schizogony,  325 

sporogony,  329 

subtertian,  334 

symptoms,  331 

tertian,  332 

tertian  parasite,  327 

treatment,  343 
Mal-de-Caderas,  357 
Malignant  disease,  298 
Malta  fever,  285 
Mania,  322 
Marrow,  95 
Mast-cells,  66 
Maurer's  dots,  329 


M'Gowan's  method  of  estimating  coagula- 
tion time,  39 
Measles,  280 

Mediterranean  fever,  285 
Megaloblasts,  62 
Meningitis,  epidemic,  284 
Meningitis,  tubercidous,  287 
Menstruation,  86 
Mercury,  300 
Merozoites,  326 
MethEemoglobinsemia,  189 
Microbic  cyanosis,  190 
Microblasts,  62 
Microgametocytes,  326 
Mixed  forms  of  leukaemia,  221 
Molecular  concentration,  44 
Mononuclear  leucocytes,  67 
Morbus  maculosus,  256 
Moribund  state,  leucocytosis,  74 
Multiple  myeloma,  237 
Mumps,  280 
Mycosis  fungoides,  319 
Myeloblastoma,  237 
Myeloblasts,  68, 108 
Myelocytes,  67 
Myelocythsemia,  209 

acute,  213 

blood  changes,  213 

chronic,  211 

diagnosis,  216 

intercurrent  disease,  216 

morbid  anatomy,  209 

pathology,  210 

prognosis,  217 

symptoms,  211 

treatment,  217 
Myelocytoma,  237 
Myeloma,  multiple,  237 
Myoma  uteri,  321 
Myxoedema,  309 

Nagana,  357 
Nematodes,  305 
Nephritis,  319 
Nervous  diseases,  321 
Neuritis,  321 
Neutrophil  leucocytes,  65 
Neutrophil  myelocytes,  67 
Newton's  rings,  6 
Nitrobenzene,  299 
Nitrous  oxide,  302 
Normoblasts,  62 
Nuclear  particles,  57 
Nucleated  red  cells,  62 
Number  of  leucocytes,  65 
Number  of  red  corpuscles,  61 
Nyctalopia,  259 

Obstruction,  intestinal,  304 
Obstruction  of  oesophagus,  303 
Obstructive  jaundice  with  anaemia,  272 
Oesophageal  obstruction,  303 
Old  age,  86 


INDEX 


383 


Oligocythemia,  62 

Oliver's  hemoglobinometer,  21 

Oliver's  tintometer,  12 

Operations,  173,  298 

Opium,  301 

Ornithodorus  moubata,  362 

Osmosis  and  erythrocytes,  55 

Osteomalacia,  324 

Osteomyelitis,  293 

Otitis  media,  294 

Ovarian  cystoma,  320 

Oxydase  reaction,  50 

Oxyuris  vermicularis,  305 

Paxchromic  staining,  35 
Pancreas,  diseases  of,  307 
Pappenheim's  pan  chromic  stain,' 35 
Pappenheim's  pipette,  12 
Paroxysmal  hemoglobinuria,  262 
Peliosis  rheumatica,  255 
Pellagra,  319 

Pelvic  inflammations,  320 
Pemphigus,  318 
Pericarditis,  287_,  294 
Peripheral  neuritis,  321 
Peritonitis,  287,  294 
Pernicious  anemia,  114 

blood  changes,  130 

complications,  140 

course,  141 

definition,  114 

diagnosis,  138 

duration,  141 

etiology,  114 

heredity,  114 

morbid  anatomy,  115 

operation  in,  152 

pathology,  118 

prognosis,  141 

salvarsan  in,  148 

sewer  gas  and,  115 

sex  incidence,  114 

splenectomy  in,  375 

symptoms,  123 

treatment,  144 
Phagocytic  anemia,  184 
Phenacetin,  299 
Phenazonum,  299 
Phosphorus,  301 
Phthisis,  287 
Piroplasmata,  372 
Plague,  285 
Plasma  cells,  68 
Plasmacytoma,  237 
Plasmodium  malarie,  328 
Plasmodium  vixax,  327 
Pleurisy,  287,  294 
Pneumonia,  314 
Poikilocytosis,  55 
Poisons,  299 
Poliomyelitis,  321 
Polychromasia,  55 
Polychromatophilia,  55 


Polycythemia,  61,  186 

Polymorphonuclear  leucocytes,  65 

Post-hemorrhagic  anemia,  169 

Potassium  chlorate,  300 

Pratt's  solution,  17 

Precipitate  method  of  estimating  alka- 
linity, 42 

Pregnancy,  86 

Primary  splenomegaly,  Gaucher  type, 
183  ' 

Primitive  leucocytes,  68 

Proportions  of  leucocytes,  70 

Prothrombin,  244 

Psoriasis,  318 

Pulmonary  phthisis,  287 

Punctate  basophilia,  56 

Purpura,  254 

Purpura  artifacta,  256 

Purpura  fulminans,  257 

Purpura  hemorrhagica,  256 

Purpura  simplex,  256 

Pyelitis,  319 

Quinine,  301 

Race,  influence  on  red  corpuscles,  61 

Recklinghausen's  disease,  319 

Red  marrow,  95 

Reichert's  condenser,  48 

Relapsing  fever,  362 

Relative  lymphocytosis,  78 

Renal  calculus,  320 

Reproductive  system,  320 

Respiratory  system,  313 

Reticular  substance  in  red  corpuscles,  57 

Rheumatism,  acute,  323 

chronic,  323 
Rheumatoid  arthritis,  323 
Rhodesian  trypanosomiasis,  360 
Rickets,  323 
Rigler's  method  of  estimating  alkalinity, 

41 
Rotheln,  280 
Rouleaux  formation,  60 

Sabrazes'  method  of  estimating  coagula- 
tion time,  39 
Sahli's  hemoglobinometer,  20 
Salines,  299 
Salpingitis,  293 

Salvarsan  in  pernicious  anemia,  148 
Samples,  withdrawal  of,  1 
Sarcoma,  296 
Scarlet  fever,  278 
Schizonts,  326 
Schonlein's  purpura,  255 
Schiiftner's  dots,  339 
Schultze's  oxydase  reaction,  51 
Scorbutus,  257 
Scurvy,  257 
Scurvy,  infantile,  260 
Secondary  anemia,  169 
Senna,  302 


384 


INDEX 


Sepsis,  290 

Septic  anaemia,  290 

Septicaemia,  290 

Shape  of  erythrocytes,  54 

Silver,  300 

Simple  secondary  anaemia,  171 

Size  of  erythrocytes,  54 

Skin  diseases,  318 

Sleeping  sickness,  357 

Smallpox,  283 

Sources  of  blood-cells,  95 

Specific  gravity,  43 

Spinal  sclerosis,  321 

Spirochetes,  362 

Spleen,  diseases  of,  309 

Splenectomy,  309 

Splenic  anaemia,  179 

blood  changes,  181 

diagnosis,  182 

Gaucher  type,  183 

morbid  anatomy,  179 

pathology,  179 

symptoms,  180 

treatment,  182 
Splenic  anaemia  of  infants,  266 
Splenocytes,  67, 104 
Splenomegalic  polycythemia,  186 
Sporonts,  326 
Sporozoites,  325 
Sprue,  304 
Stained  films,  27 
Staining,  30,  377 
Status  lymphaticus,  274 
Status  thymicus,  274 
Stomatitis,  303 

Strong  and  Seligman's  method  of  count- 
ing leucocytes,  16 
Sulphhaemoglobinaemia,  171 
Surra,  357 

Symptomatic  anaemia,  190 
Syphilis,  288 

Tabes  mesenterica,  287 

Taenia  echinococcus,  306 

Taenia  mediocanellata,  306 

Taenia  solium,  306 

Tallqvist's  haemoglobinometer,  24 

Tetanus,  285 

Thoma-Zeiss  haemocytometer,  4 

Thomson's  pipette,  338 

Thrombin,  243 

Thrombokinase,  244 

Thymus  tod,  275 

Tick  fever,  365 

Tintometer,  Oliver's,  12 

Toisson's  solution,  4 


Tonsillitis,  303 

Total  quantity  of  blood  in  the  body,  47 

Transitional  leucocytes,  67 

Trichina  spiralis,  306 

Trichocephalus  dispar,  306 

Trophozoites,  326 

Trypanosoma  Brucei,  357 

cuniculi,  356 

equinum,  357 

equiperdum,  357 

Evansi,  357 

Lewisi,  356 

nanum,  357 

pecorum,  357 

Theileri,  357 

vivax,  357 
Trypanosomiasis,  356 

Rhodesian,  360 

South  American,  360 
Tuberculosis,  286 
Turk's  counting  chamber,  11 
Turton's  method  of  counting  leucocytes, 

16 
Typhoid  fever,  281 
Typhus,  283 

Urinary  system,  319 

Vaccination,  283 

Varicella,  283 

Variola,  283 

Vasomotor    effect    on    number    of    red 

corpuscles,  61 
Viscosimeter,  38 
Viscosity  of  blood,  38 
Vital  staining,  52 
Volume  index,  13 

Von  Flieschl's  haemoglobinometer,  20 
Von  Jaksch's  anemia,  266 

Watson  and  Denning's  viscosimeter,  38 
Weidenreich's  theory,  54 
Werlhof's  diseese,  256 
"Wet  staining  methods,  35 
Whooping-cough,  280 
Withdrawal  of  samples,  1 
Wounds,  298 

Wright's  method  of  estimating  coagula- 
tion time,  40 

Yellow  fever,  284 
Yellow  marrow,  95 

Zappert's  counting  chamber,  11 
Zenker's  degeneration    in    lymphatism> 
275 


PRINTED   BY   GREEN   AND   SON,   EDINBURGH 


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